Biology

Review part 2
(by some wiki material, Essential Cell Biology, and personal adds)

(May the force be with us)

The endoplasmic reticulum

The endoplasmic reticulum is a network of tubules and flattened sacs that serve a variety of functions in the cell. There are two regions of the ER that differ in both structure and function. One region is called rough ER because it has ribosomes attached to the cytoplasmic side of the membrane. The other region is called smooth ER because it lacks attached ribosomes. Typically, the smooth ER is a tubule network and the rough ER is a series of flattened sacs. The space inside of the ER is called the lumen. The ER is very extensive extending from the cell membrane through the cytoplasm and forming a continuous connection with the nuclear envelope. Since the ER is connected with the nuclear envelope, the lumen of the ER and the space inside the nuclear envelope are part of the same compartment. The rough endoplasmic reticulum manufactures membranes and secretory proteins. In leukocytes the rough ER produces antibodies. In pancreatic cells the rough ER produces insulin. The rough and smooth ER are usually interconnected and the proteins and membranes made by the rough ER move into the smooth ER to be transferred to other locations. The smooth ER has a wide range of functions including carbohydrate and lipid synthesis. It serves as a transitional area for vesicles that transport ER products to various destinations. In liver cells the smooth ER produces enzymes that help to detoxify certain compounds. In muscles the smooth ER assists in the contraction of muscle cells, and in brain cells it synthesizes male and female hormones.

Some key features: The ER itself is a network of sacs, tubules and vesicles surrounded by a single membrane that separates ER lumen from the cytosol The rough ER has ribosomes that synthesize proteins destined for the plasma membrane (SNAP and SNARE proteins), for secretion, or for various organelles of the endomembrane system Both the rough and smooth ER synthesizes lipids for cellular membranes The smooth ER is also the site of drug detoxification, carbohydrate metabolism, calcium storage, steroid biosynthesis in some cells Before protein leave the ER in transition vesicles, they undergo the first few steps of protein modification. ER- specific proteins catalyze core glycosylation and folding of polypeptides, elimination of mis-folded proteins and the assembly of multimeric ones Medical Applications I could find only this serious note, Im sure it has many others related to drug detoxification and so on, but I cannot find better for the moment The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum. The UPR is activated in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum. In this scenario, the UPR has two primary aims: initially to restore normal function of the cell by halting protein translation and activate the signaling pathways that lead to increasing the production of molecular chaperones involved in protein folding. If these objectives are not achieved within a certain time lapse or the disruption is prolonged, the UPR aims to apoptosis.


Some more material to read

The endoplasmic reticulum (ER), the entrance site for proteins destined to reside in the secretory pathway or the extracellular environment, is also the site of biosynthesis for steroids and for cholesterol and many lipids. Given the considerable number of resident structural proteins and biosynthetic enzymes and the high expression of many secreted proteins, the total concentration of proteins in this organelle can reach 100 mg/ml. The ER relies on an efficient system of protein chaperones that prevent the accumulation of unfolded or aggregated proteins and correct misfolded proteins that are caught in low-energy kinetic traps. These chaperone- mediated processes expend metabolic energy to ensure high-fidelity protein folding in the lumen of the ER. For example, the most abundant ER chaperone, BiP/GRP78, uses the energy from ATP hydrolysis to promote folding and prevent aggregation of proteins within the ER. In addition, the oxidizing environment of the ER creates a constant demand for cellular protein disulfide isomerases to catalyze and monitor disulfide bond formation in a regulated and ordered manner. Operating in parallel with chaperone-dependent protein folding are several quality control mechanisms, which ensure that, of all proteins translocated into the ER lumen, only those that are properly folded transit to the Golgi compartment. Proteins that are misfolded in the ER are retained until they reach their native conformation or are retrotranslocated back into the cytosol for degradation by the 26S proteasome. The ER has evolved highly specific signaling pathways to ensure that its protein-folding capacity is not overwhelmed. These pathways, collectively termed the unfolded protein response (UPR), are required if the cell is to survive the ER stress that can result from perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, or altered glycosylation. Upon accumulation of unfolded proteins in the ER lumen, the UPR is activated, reducing the amount of new protein translocated into the ER lumen, increasing retrotranslocation and degradation of ER-localized proteins, and bolstering the protein- folding capacity of the ER. The UPR is orchestrated by the coordinate transcriptional activation of multiple genes, a general decrease in translation initiation, and a concomitant shift in the mRNAs that are translated.

Golgi Apparatus The Golgi apparatus (GA), also called Golgi body or Golgi complex and found universally in both plant and animal cells, is typically comprised of a series of five to eight cup- shaped, membrane-covered sacs called cisternae that look something like a stack of deflated balloons. In some unicellular flagellates, however, as many as 60 cisternae may combine to make up the Golgi apparatus. Similarly, the number of Golgi bodies in a cell varies according to its function. Animal cells generally contain between ten and twenty Golgi stacks per cell, which are linked into a single complex by tubular connections between cisternae. This complex is usually located close to the cell nucleus.

Due to its relatively large size, the Golgi apparatus was one of the first organelles ever observed. In 1897, an Italian physician named Camillo Golgi, who was investigating the nervous system by using a new staining technique he developed (and which is still sometimes used today; known as Golgi staining or Golgi impregnation), observed in a sample under his light microscope a cellular structure that

he termed the internal reticular apparatus. Soon after he publicly announced his discovery in 1898, the structure was named after him, becoming universally known as the Golgi apparatus. Yet, many scientists did not believe that what Golgi observed was a real organelle present in the cell and instead argued that the apparent body was a visual distortion caused by staining. The invention of the electron microscope in the twentieth century finally confirmed that the Golgi apparatus is a cellular organelle. The Golgi apparatus is often considered the distribution and shipping department for the cell's chemical products. It modifies proteins and lipids (fats) that have been built in the endoplasmic reticulum and prepares them for export outside of the cell or for transport to other locations in the cell. Proteins and lipids built in the smooth and rough endoplasmic reticulum bud off in tiny bubble-like vesicles that move through the cytoplasm until they reach the Golgi complex. The vesicles fuse with the Golgi membranes and release their internally stored molecules into the organelle. Once inside, the compounds are further processed by the Golgi apparatus, which adds molecules or chops tiny pieces off the ends. When completed, the product is extruded from the GA in a vesicle and directed to its final destination inside or outside the cell. The exported products are secretions of proteins or glycoproteins that are part of the cell's function in the organism. Other products are returned to the endoplasmic reticulum or may undergo maturation to become lysosomes.

 The modifications to molecules that take place in the Golgi apparatus occur in an orderly fashion. Each Golgi stack has two distinct ends, or faces. The cis face of a Golgi stack is the end of the organelle where substances enter from the endoplasmic reticulum for processing, while the trans face is where they exit in the form of smaller detached vesicles. Consequently, the cis face is found near the endoplasmic reticulum, from whence most of the material it receives comes, and the trans face is positioned near the plasma membrane of the cell, to where many of the substances it modifies are shipped. The chemical make-up of each face is different and the enzymes contained in the lumens (inner open spaces) of the cisternae between the faces are distinctive. Illustrated in Figure 2 is a fluorescence digital image taken through a microscope of the Golgi apparatus (pseudocolored red) in a typical animal cell. Note the close proximity of the Golgi membranes to the cell nucleus. Proteins, carbohydrates, phospholipids, and other molecules formed in the endoplasmic reticulum are transported to the Golgi apparatus to be biochemically modified during their transition from the cis to the trans poles of the complex. Enzymes present in the Golgi lumen modify the carbohydrate (or sugar) portion of glycoproteins by adding

or subtracting individual sugar monomers. In addition, the Golgi apparatus manufactures a variety of macromolecules on its own, including a variety of polysaccharides. The Golgi complex in plant cells produces pectins and other polysaccharides specifically needed by for plant structure and metabolism. The products exported by the Golgi apparatus through the trans face eventually fuse with the plasma membrane of the cell. Among the most important duties of the Golgi apparatus is to sort the wide variety of macromolecules produced by the cell and target them for distribution to their proper location. Specialized molecular identification labels or tags, such as phosphate groups, are added by the Golgi enzymes to aid in this sorting effort.

Cell Secretion

(This is more complicated than you could imagine, so Ill try to condense it under some of the most important steps of this huge and tricky process)

First of all a super synthesis (useful to review what you found above):

1. Cell secretion is the elimination to the exterior of substances produced by the cell (for example, hormones, mucus, sweat, etc.) 2. In secretory cells, like the secretory cells of endocrine glands, organelles related to production, processing and exportation of substances are widely present and well-developed. These organelles are the rough endoplasmic reticulum and the Golgi apparatus. The nuclear membrane of the secretory cells generally has more pores to allow the intense traffic of molecules related to protein synthesis between the cytoplasm and the nucleus. 3. The rough endoplasmic reticulum has in its outer membrane numerous ribosomes, structures where translation of messenger RNA and protein synthesis occur. These proteins are stored in the rough endoplasmic reticulum and later they go to the Golgi apparatus. Within the Golgi apparatus proteins are chemically transformed and when ready they are put inside vesicles that detach from the organelle. These vesicles fuse with the plasma membrane (exocytosis) in the right place and its content is liberated outside the cell. 4. Endocrine and exocrine pancreatic cells, thyroid and parathyroid endocrine cells, adenohypophysis, adrenal and pineal endocrine cells, the many types of gastric exocrine and endocrine cells, the mucus secretory cells of the lungs and of the bowels, the salivary gland cells, the lacrimal gland cells, the sebaceous gland cells, the secretory cells of the ovaries and testicles, etc., are all examples of secretory cells.

Now lets take a further look at the entire process:

Trafficking through the endomembrane system 1. Vesicles carry lipids and proteins along several routes from the ER through the Golgi Complex to various destinations, including secretory vesicles, endosomes and lysosomes 2. Proteins are synthesized by ribosomes attached to the cytosolic surface of the rough ER. Initial glycosylation steps occur within the ER lumen 3. Transition vesicles carry newly synthesized lipids and glycosylated proteins to the CGN (what is this? Be cool guys: Cys-Golgi-Network) 4. Lipids and proteins move through the cisternae of the Golgi stack via shuttle vesicles or as cisternae mature.

5. 6. 7. 8. 9.

Ate the TGN (or simply Trans-Golgi-Network), vesicles bud off to form secretory vesicles, or endosomes, depending on their protein content Secretory vesicles move to the plasma membrane, where they release their contents by exocytosis, either constitutively or in response to an appropriate signal Proteins and other materials are taken into the cell by endocytosis, forming endocytic vesicles that fuse with early endosomes Cellular components not designed for digestion following endocytosis are recycled to the plasma membrane Early endosomes containing material for digestion mature to form late endosomes and then lysosomes Retrograde traffic returns compartiment-specific proteins to earlier compartments

There is a constitutive secretion, in which the process of secretion is continue, unregulated by extracellular signals (i.e. mucus release by intestine) And a regulated secretion, when the vesicles are first accumulated in the cell and then fuse with the membrane only in response of specific extracellular signals (i.e. neurotransmitters) Exocytosis: vesicles are released to the exterior of the cell by fusing with the inner membrane. Generally triggered by the elevation of calcium ions into the cell. In many cases it is limited to a specific surface of the cell, the so called polarized secretion Endocytosis: materials are up taken from the outer of the cell to the inner side by the formation of a vesicle starting from the plasma membrane folding inward. Usually we talk about phagocytosis to describe the abovementioned process. Hence the receptor-mediated

endocytosis depends on highly specific binding of ligands to corresponding receptors on the cell surface. Lysosomes
Introduction:

The lysosome is a membranous bag which contains hydrolytic enzymes that are used to digest macromolecules. The lysosome contains over 40 enzymes, some of which are the proteases, nucleases, and phopholipases. These enzymes optimally work at a pH of 5 (acidic), so should these enzymes leak out they would cause minimal damage to the cytoplasm. These enzymes, called hydrolases, are made in the ER and transported to the lysosome by the Golgi complex, using a vesicle. Should certain hydrolases be missing from the cells, serious illness can occur because of a buildup of molecules, which cannot be digested by the lysosome. These extra molecules can interfere with normal cell functions, causing problems.

Lysosomes contain an ionic pump, which maintains a highly acidic pH. Lysosomes have 2 main roles: To digest macromolecules that enter the cell: they are like sacs, which contain around forty digestive enzymes. The lysosomes infuse with vesicles of engulfed material and release the digestive enzymes to break up the material. The large molecules of food are broken down into smaller particles. The products diffuse through the lysosomes' membrane and are distributed throughout the rest of the cell. The products serve as building blocks of new materials.

 To breakdown old nonfunctioning organelle that out lived their usefulness- Cells fail to restore themselves causing them to age. Because of this lysosomes are needed to rid the cell of these unneeded materials that are occupying space in the cell. In stressed or dying cells' membrane, this component of the cell denigrates material, releasing the destructive lysosomal enzymes into the cytoplasm. Here they digest all organelles and speed up the cells' death by this process of autolysis (self-digestion). The products are recycled and reused to compose new parts of cells. The Golgi apparatus forms lysosomes. There are primary and secondary lysosomes. The primary are formed on the rough ER (endoplasmic reticulum). The secondary lysosomes are formed on the smooth ER by following the phagocytosis (process of taking solid materials into cells). Phagosomes fuse with lysosomes and work as one digestive vacuole. Lysosomal enzymes are released into this vacuole in order to digest the bacteria or other materials. Small molecules which are the result leave the vacuole through its membrane and are used to make new molecules. The indigestible materials are deposited outside the cell. Diseases: There are many diseases related to the malfunctioning of lysosomes. There are fifty overall. They are characterized by specific enzyme deficiencies. These diseases show characteristic patterns of the accumulation of polysaccharides or lipids in the tissues of nerve cells, muscle, liver, or spleen. Some of these diseases are arthritis, Hurler's syndrome, Tay-sachs, Pompe's disease, cystic fibroses, silicosis, asbestosis, and lysosomal storage disease.

Peroxisomes In 1965, Christian de Duve and his colleagues found other enzymes containing organelle. They called these peroxisomes because they seemed to generate and break down hydrogen peroxide. Peroxisomes, also known as microbodies, and they are self replicating cells containing oxidative enzymes. They are similar to lysosomes. Their enzymes have two functions; to convert fats to carbohydrates and to detoxify potentially harmful molecules which form in the cell. Peroxisomes, in contrast to lysosomes, are produced only on the smooth ER system. They are found in the cytoplasm of many eukaryotic cells as well as prokaryotic cells, microorganisms, and plant cells. They are very active in yeast, protozoans, kidney cells, and mammailain cells. Peroxisomes are permeable. This allows many small molecules to enter easily. The enzyme of peroxisomes removes hydrogen atoms from small molecules and joins them to oxygen creating hydrogen peroxide. They consume up to twenty percent of the oxygen in the liver cell. The peroxisomal enzyme catalase uses this oxygen to convert hydrogen peroxide to water and oxygen neutralizing it. In the liver this method is used to break down molecules of alcohol into substances that can be eliminated from the body. Diseases: The rare fatal genetic disorder Zellweger's syndrome is the result of malformed peroxisomes. This indicates peroxisomes do have an important role in healthy cells.

Mitochondria Mitochondria are rod-shaped organelles that can be considered the power generators of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy "currency" of the cell that powers the cell's metabolic activities. This process is called aerobic respiration and is the reason animals breathe oxygen. Without mitochondria (singular, mitochondrion), higher animals would likely not exist because their cells would only be able to obtain energy from anaerobic respiration (in the absence of oxygen), a process much less efficient than aerobic respiration. In fact, mitochondria enable cells to produce 15 times more ATP than they could otherwise, and complex animals, like humans, need large amounts of energy in order to survive. The number of mitochondria present in a cell depends upon the metabolic requirements of that cell, and may range from a single large mitochondrion to thousands of the organelles. Mitochondria, which are found in nearly all eukaryotes, including plants, animals, fungi, and protists, are large enough to be observed with a light microscope and were first discovered in the 1800s. The name of the organelles was coined to reflect the way they looked to the first scientists to observe them, stemming from the Greek words

for "thread" and "granule." For many years after their discovery, mitochondria were commonly believed to transmit hereditary information. It was not until the mid- 1950s when a method for isolating the organelles intact was developed that the modern understanding of mitochondrial function was worked out. The elaborate structure of a mitochondrion is very important to the functioning of the organelle (see Figure 1). Two specialized membranes encircle each mitochondrion present in a cell, dividing the organelle into a narrow intermembrane space and a much larger internal matrix, each of which contains highly specialized proteins. The outer membrane of a mitochondrion contains many channels formed by the protein porin and acts like a sieve, filtering out molecules that are too big. Similarly, the inner membrane, which is highly convoluted so that a large number of infoldings called cristae are formed, also allows only certain molecules to pass through it and is much more selective than the outer membrane. To make certain that only those materials essential to the matrix are allowed into it, the inner membrane utilizes a group of transport proteins that will only transport the correct molecules. Together, the various compartments of a mitochondrion are able to work in harmony to generate ATP in a complex multi-step process. Mitochondria are generally oblong organelles, which range in size between 1 and 10 micrometers in length, and occur in numbers that directly correlate with the cell's level of metabolic activity. The organelles are quite flexible, however, and time-lapse studies of living cells have demonstrated that mitochondria change shape rapidly and move about in the cell almost constantly. Movements of the organelles appear to be linked in some way to the microtubules present in the cell, and are probably transported along the network with motor proteins. Consequently, mitochondria may be organized into lengthy traveling chains, packed tightly into relatively stable groups,

or appear in many other formations based upon the particular needs of the cell and the characteristics of its microtubular network.

Presented in Figure 2 is a digital image of the mitochondrial network found in the ovarian tissue from a mountain goat relative, known as the Himalayan Tahr, as seen through a fluorescence optical microscope. The extensive intertwined network is labeled with a synthetic dye named MitoTracker Red (red fluorescence) that localizes in the respiring mitochondria of living cells in culture. The rare twin nuclei in this cell were counterstained with a blue dye (cyan fluorescence) to denote their centralized location in relation to the mitochondrial network. Fluorescence microscopy is an important tool that scientists use to examine the structure and function of internal cellular organelles. The mitochondrion is different from most other organelles because it has its own circular DNA (similar to the DNA of prokaryotes) and reproduces independently of the cell in which it is found; an apparent case of endosymbiosis. Scientists hypothesize that millions of years ago small, free- living prokaryotes were engulfed, but not consumed, by larger prokaryotes, perhaps because they were able to resist the digestive enzymes of the host organism. The two

organisms developed a symbiotic relationship over time, the larger organism providing the smaller with ample nutrients and the smaller organism providing ATP molecules to the larger one. Eventually, according to this view, the larger organism developed into the eukaryotic cell and the smaller organism into the mitochondrion. Mitochondrial DNA is localized to the matrix, which also contains a host of enzymes, as well as ribosomes for protein synthesis. Many of the critical metabolic steps of cellular respiration are catalyzed by enzymes that are able to diffuse through the mitochondrial matrix. The other proteins involved in respiration, including the enzyme that generates ATP, are embedded within the mitochondrial inner membrane. Infolding of the cristae dramatically increases the surface area available for hosting the enzymes responsible for cellular respiration. Mitochondria are similar to plant chloroplasts in that both organelles are able to produce energy and metabolites that are required by the host cell. As discussed above, mitochondria are the sites of respiration, and generate chemical energy in the form of ATP by metabolizing sugars, fats, and other chemical fuels with the assistance of molecular oxygen. Chloroplasts, in contrast, are found only in plants and algae, and are the primary sites of photosynthesis. These organelles work in a different manner to convert energy from the sun into the biosynthesis of required organic nutrients using carbon dioxide and water. Like mitochondria, chloroplasts also contain their own DNA and are able to grow and reproduce independently within the cell. In most animal species, mitochondria appear to be primarily inherited through the maternal lineage, though some recent evidence suggests that in rare instances mitochondria may also be inherited via a paternal route. Typically, a sperm carries mitochondria in its tail as an energy source for its long journey to the egg. When the sperm attaches to the egg during fertilization, the tail falls off. Consequently, the only

mitochondria the new organism usually gets are from the egg its mother provided. Therefore, unlike nuclear DNA, mitochondrial DNA doesn't get shuffled every generation, so it is presumed to change at a slower rate, which is useful for the study of human evolution. Mitochondrial DNA is also used in forensic science as a tool for identifying corpses or body parts, and has been implicated in a number of genetic diseases, such as Alzheimer's disease and diabetes. Diseases: Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that are the "powerhouses". Mitochondria are found in every cell of the body except red blood cells. Mitochondria convert the energy of food molecules into the ATP that powers most cell functions. Mitochondrial diseases are often caused by genetics or mutations to the mitochondrial DNA that affect mitochondria function. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often called a mitochondrial myopathy. There is some evidence for mitochondrial dysfunction as the molecular basis of bipolar disorder. In addition, classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits, i.e: Diabetes mellitus and deafness (DAD) Leber's hereditary optic neuropathy (LHON) Leigh syndrome, subacute sclerosing encephalopathy Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)

 Myoneurogenic gastrointestinal encephalopathy (MNGIE) Myoclonic Epilepsy with Ragged Red Fibers (MERRF) Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS) Extra Cellular Matrix (ECM) The extracellular matrix (ECM) is a complex structural entity surrounding and supporting cells that are found within mammalian tissues. The ECM is often referred to as the connective tissue. The ECM is composed of 3 major classes of biomolecules: 1. Structural proteins: collagen and elastin. 2. Specialized proteins: e.g. fibrillin, fibronectin, and laminin. 3. Proteoglycans: these are composed of a protein core to which is attached long chains of repeating disaccharide units termed of glycosaminoglycans (GAGs) forming extremely complex high molecular weight components of the ECM. Collagens are the most abundant proteins found in the animal kingdom. It is the major protein comprising the ECM. There are at least 30 different collagen genes dispersed through the human genome. These 30 genes generate proteins that combine in a variety of ways to create over 20 different types of collagen fibrils. Types I, II and III are the most abundant and form fibrils of similar structure. Type IV collagen forms a two-dimensional reticulum and is a major component of the basal lamina. Collagens are predominantly synthesized by fibroblasts but epithelial cells also synthesize these proteins. The fundamental higher order structure of collagens is a long and thin diameter rod-like protein. Collagens are synthesized as longer precursor proteins called procollagens. Type I procollagen contains an

additional 150 amino acids at the N-terminus and 250 at the C-terminus. These pro-domains are globular and form multiple intrachain disulfide bonds. The disulfides stabilize the proprotein allowing the triple helical section to form. Elastin Many tissues, such as skin, lung and blood vessels, need to be both strong and elastic to function properly. A network of elastic fibres in the ECM of these tissues gives them the required resilience to recoil after stretching. The main component of elastic fibres is the elastin molecule, which creates cross-links to adjacent elastin molecules. These molecules form a core of elastic fibres and are covered by fibrillin, a large glycoprotein that binds to elastin and is essential for the integrity of elastic fibres. Fibronectin The role of fibronectins is to attach cells to a variety of extracellular matrices. Fibronectin attaches cells to all matrices except type IV that involves laminin as the adhesive molecule. Fibronectins are dimers of 2 similar peptides. Each chain is 60-70nm long and 2-3nm thick. At least 20 different fibronectin chains have been identified that arise by alternative RNA splicing of the primary transcript from a single fibronectin gene. Fibronectins contain at least 6 tightly folded domains each with a high affinity for a different substrate such as heparan sulfate, collagen (separate domains for types I, II and III), fibrin and cell-surface receptors. The cell-surface receptor- binding domain contains a consensus amino acid sequence, RGDS.

Laminin All basal laminae contain a common set of proteins and GAGs. These are type IV collagen, heparan sulfate proteoglycans, entactin and laminin. The basal lamina is often refered to as the type IV matrix. Each of the components of the basal lamina is synthesized by the cells that rest upon it. Laminin anchors cell surfaces to the basal lamina. GAGs (Glycosaminoglicans) Glycosaminoglycans (GAGs) are composed of polysaccharide chains made up of repeating disaccharide units and are strongly hydrophilic. GAGs are highly negatively charged and therefore attract osmotically active Na+, causing large amounts of water to be drawn into their structure. This results in GAGs occupying a huge volume relative to their mass and forming gels at very low concentrations. The hydrophilic nature of GAGs causes a swelling pressure, or turgor, which enables the ECM to withstand compression forces. The cartilage matrix lining the knee joint, for example, can support pressures of hundreds of atmospheres because of its high GAG content. Hyaluronic acid (HA), a chief component of the ECM, is a large GAG that attracts water and is found in increased amounts in damaged or growing tissues. HA stimulates cytokine production by macrophages, thereby promoting angiogenesis. Proteoglycans Proteoglycans retain water and form a gel-like substance through which ions, hormones and nutrients can move freely. Given the great abundance and structural diversity of proteoglycan molecules, it would be surprising if their

function was limited to providing lubrication around and between cells. Perlecan is a proteoglycan present in the basement membrane, where it forms a gel of varying pore size and charge density. The epidermal cells of the skin derive their metabolic nutrients from the dermis via the diffusion of molecules through the basement membrane, so proteoglycans may play a key role in selectively filtering molecules that pass through the basement membrane beneath the epidermal cells. Proteoglycans also appear to have an important role in regulating signalling between cells. For example, the heparin sulphate chains of proteoglycans bind to several different growth factors, including fibroblast growth factors (FGFs), helping them to bind to their specific cell-surface receptors Clinical Significance of Collagen Disorders Collagens are the most abundant proteins in the body. Alterations in collagen structure resulting from abnormal genes or abnormal processing of collagen proteins results in numerous diseases, e.g. Alport syndrome, Larsen syndrome, and numerous chondrodysplasias as well as the more commonly known clusters of related syndromes of osteogenesis imperfecta and Ehlers-Danlos syndrome. Ehlers-Danlos syndrome (EDS) is actually the name associated with at least ten distinct disorders that are biochemically and clinically distinct yet all manifest structural weakness in connective tissue as a result of defects in the structure of collagens. Osteogenesis imperfecta (OI) also encompasses more than one disorder. At least four biochemically and clinically distinguishable disorders have been identified and are identified as type I (mild), type II (perinatal lethal), type III (deforming), and type IV (mild deforming. All four forms are characterized by multiple fractures and resultant bone deformities.

 Marfan syndrome (MFS) manifests itself as a disorder of the connective tissue and was believed to be the result of abnormal collagens. However, recent evidence has shown that MFS results from mutations in the extracellular protein, fibrillin, which is an integral constituent of the non- collagenous microfibrils of the extracellular matrix. Basal Membrane
(This name have no sense in my opinion, I think it is written instead of lamina propria or basolateral membrane, the cellular membrane is a large topic and I dont want to loose time here, I will focus on what is important and correlated with the next chapters)

Generically: The cell membrane surrounds the protoplasm of a cell and, in animal cells, physically separates the intracellular components from the extracellular environment. Fungi, bacteria and plants also have the cell wall, which provides a mechanical support for the cell and precludes passage of the larger molecules. The cell membrane also plays a role in anchoring the cytoskeleton to provide shape to the cell, and in attaching to the extracellular matrix and other cells to help group cells together to form tissues. The barrier is differentially permeable and able to regulate what enters and exits the cell, thus facilitating the transport of materials needed for survival. The movement of substances across the membrane can be either passive, occurring without the input of cellular energy, or active, requiring the cell to expend energy in moving it. The membrane also maintains the cell potential. The cell membrane works as a selective filter that allows only certain things to come inside or go outside the cell, it is important in maintaining a homeostatic environment in the cell to keep us healthy and alive.

 Further. The Basal Lamina: The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below. It is typically about 40-50 nanometers thick (with exceptions such as the basal laminae that compose the 100- 200 nanometre thick glomerular basement membrane). It includes proteoglycans.
(Thats what we need! Read below!)

Laminins One of the major adhesive glycoprotein present in ECM is a family of proteins called laminins, which are conserved from simple invertebrates to humas. Unlike fibronectins (read the chapter of ECM), which occur widely throughout supporting tissues and body fluids, laminins are found mainly in the basal lamina. This thin sheet of specialized extracellular material (about 50nm thick), underlies epithelial cells, thereby separating them from connective tissues. Basal laminae also surround muscle cells, fat cells and the Schwann cells. Cell Adhesion Cell adhesion molecules are glycoproteins expressed on the cell surface and play a critical role in a wide array of biologic processes that include hemostasis, the immune response, inflammation, embryogenesis, and development of neuronal tissue. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. Membrane proteins that mediate immune cellcell interactions fall into different categories, namely those

involved in antigen recognition, costimulation and cellular adhesion. Furthermore cell-cell adhesions are important for brain morphology and highly coordinated brain functions such as memory and learning. During early development of the nervous system, neurons elongate their axons towards their targets and establish and maintain synapses through formation of cell-cell adhesions. Cell-cell adhesions also underpin axon-axon contacts and link neurons with supporting Schwann cells and oligodendrocytes.
(To check how many of them we find in the human body and why I did not mentioned the classification just check this site and scream freely: http://www.genome.jp/kegg/pathway/hsa/hsa04514.html) (Now a problem ruined my mind around 3 am have I got to write something about cell-to-cell junctions??? It is not mentioned at all in the chapters but I still can remember some discussion about them at lesson I got to save my soul somehow; so sorry for that but I have to type only some key features)

Cell-cell junctions There are three general types: adhesive, tight and gap: Adhesive junctions: such as adherens and desmosomes that use cadherins to hold cells together Adhesive junctions are anchored to the cytoskeleton by linker proteins that attach to actin microfilaments (adherens) or intermediate filaments (desmosomes) Desmosomes are particularly prominent in tissues that must withstand (be capable to resist) considerable mechanical stresses Tight junctions form a permeability barrier between epithelial cells, and they prevent lateral movement of membrane proteins, thereby partitioning the membrane into discrete functional domains Gap junctions form open channels between cells, allowing direct chemical and electrical communication between cells. Its permeability is limited to ions and small molecules

Cell to ECM junctions: (once again) The ECM is held in place by adhesive glycoproteins such as fibronectins, which link cells to the ECM and laminins, which attach cells to the basal lamina. Cells use surface receptor glycoproteins called integrins to connect to the ECM. Integrins, like cadherins, attach to the cytoskeleton via linker proteins. Focal adhesion connect to actin, and hemidesmosomes connect to intermediate filaments. Cell adhesion clinical implications (hard to find)

Dysfunction of cell-adhesion and cell-migration occurs during cancer metastasis. Cellular adhesion and traction can allow cells to migrate. Cells can form intergrin mediated attachments sites called focal adhesions. Focal adhesions at the leading edge provide the necessary traction allowing the cell to pull its self forward. Pemphigus is the result of auto-antibodies which target desmosomal cadherins. Results in loss of cell adhesion.
Some more possible diseases due to CAMs (cell adhesion molecules): Cell adhesion molecules of the liver and their role in hepatocarcinogenesis and inflammatory liver disease Infection and fibrosis and with transforming growth factor beta (TGF-beta) Molecular basis of Cancer

Cell-cell recognition (my arm is so sweat that is fused with the book) It is maybe the most difficult chapter to talk about, most of the key features are explained in the previous chapter about cell-cell adhesion, hence I will type only few words about real interactions and classes of cell-cell contact. The classes of transmembrane proteins responsible of interactions between cells are: Immunoglobulin superfamily (IgSF) Cadherins Selectins Integrins (few cases) In each case, the adhesion protein on the surface of one cell binds to the appropriate ligand on the surface of a neighboring cell. So we will find: Hemophilic interactions, such as many cadherins and IgSF, in this case cells interact with identical molecules on the surface of the cell that they adhere to! Heterophilic intercations, such as selectins and integrins where a cell adhesion receptor on one cell interact with a different molecule on the surface of the other cell

***Remember one well-known example really familiar to every one of our class: ABO grouping !!! Here the carbohydrates residues on the glycolipid of the plasma membrane of erythrocytes is specific in each group, i.e: A type: N-acetylgalactosamide B type: galactose 0 type ???? : no one sugar in the residues!!! AB type: both!

Another medical application I found: enteropathogenic bacteria use normal cell adhesion to infect host cells! For example the Yersinia express a protein called invasion to attach the integrin of the enteric epithelia.

Cellular senescence and medical implication

I cant continue guys sorry but Im dropping dead on the desk its 4 o clock antemeridian and I need to sleep, if I can Ill finish this review tomorrow in the early afternoon and Il post it as usual Give some extra-hours for the medical application and do not forget the fundamentals of each chapter if you want to face the exam Your beloved dead colleague, Alessandro Motta