Agrin

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AGRN
Agrincartoon2.png
Identifiers
Aliases AGRN, CMS8, CMSPPD, agrin
External IDs OMIM: 103320 MGI: 87961 HomoloGene: 27907 GeneCards: AGRN
Gene location (Human)
Chromosome 1 (human)
Chr. Chromosome 1 (human)[1]
Chromosome 1 (human)Genomic location for AGRNGenomic location for AGRN
Band 1p36.33 Start 1,020,120 bp[1]
End 1,056,118 bp[1]
Gene location (Mouse)
Gene ontology
Orthologs
Species Human Mouse
Entrez
375790

11603

Ensembl
ENSG00000188157

ENSMUSG00000041936

UniProt
O00468

A2ASQ1

RefSeq (mRNA)
NM_001305275
NM_198576
NM_001364727

NM_021604
NM_001369026
NM_001369027

RefSeq (protein)
NP_001292204
NP_940978
NP_001351656

NP_067617
NP_001355955
NP_001355956

Location (UCSC) Chr 1: 1.02 � 1.06 Mb Chr 4: 156.17 � 156.2 Mb

PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Agrin NtA domain
Identifiers
Symbol NtA
Pfam PF03146
InterPro IPR004850
SCOPe 1jc7 / SUPFAM
Available protein structures:
Agrin is a large proteoglycan whose best-characterised role is in the development
of the neuromuscular junction during embryogenesis. Agrin is named based on its
involvement in the aggregation of acetylcholine receptors during synaptogenesis. In
humans, this protein is encoded by the AGRN gene.[5][6][7]

This protein has nine domains homologous to protease inhibitors.[8] It may also
have functions in other tissues and during other stages of development. It is a
major proteoglycan component in the glomerular basement membrane and may play a
role in the renal filtration and cell-matrix interactions.[9]

Contents
1 Discovery
2 Mechanism of action
3 Signaling
4 Structure
5 References
6 External links
Discovery
Agrin was first identified by the U.J. McMahan laboratory, Stanford University.[10]

Mechanism of action
During development in humans, the growing end of motor neuron axons secrete a
protein called agrin.[11] When secreted, agrin binds to several receptors on the
surface of skeletal muscle. The receptor which appears to be required for the
formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle
specific kinase).[12][13] MuSK is a receptor tyrosine kinase - meaning that it
induces cellular signaling by causing the addition of phosphate molecules to
particular tyrosines on itself and on proteins that bind the cytoplasmic domain of
the receptor.

In addition to MuSK, agrin binds several other proteins on the surface of muscle,
including dystroglycan and laminin. It is seen that these additional binding steps
are required to stabilize the NMJ.

The requirement for Agrin and MuSK in the formation of the NMJ was demonstrated
primarily by knockout mouse studies. In mice that are deficient for either protein,
the neuromuscular junction does not form.[14] Many other proteins also comprise the
NMJ, and are required to maintain its integrity. For example, MuSK also binds a
protein called "dishevelled" (Dvl), which is in the Wnt signalling pathway. Dvl is
additionally required for MuSK-mediated clustering of AChRs, since inhibition of
Dvl blocks clustering.

Signaling
The nerve secretes agrin, resulting in phosphorylation of the MuSK receptor.

It seems that the MuSK receptor recruits casein kinase 2, which is required for
clustering.[15]

A protein called rapsyn is then recruited to the primary MuSK scaffold, to induce
the additional clustering of acetylcholine receptors (AChR). This is thought of as
the secondary scaffold. A protein called Dok-7 has shown to be additionally
required for the formation of the secondary scaffold; it is apparently recruited
after MuSK phosphorylation and before acetylcholine receptors are clustered.

Structure
There are three potential heparan sulfate (HS) attachment sites within the primary
structure of agrin, but it is thought that only two of these actually carry HS
chains when the protein is expressed.

In fact, one study concluded that at least two attachment sites are necessary by
inducing synthetic agents. Since agrin fragments induce acetylcholine receptor
aggregation as well as phosphorylation of the MuSK receptor, researchers spliced
them and found that the variant did not trigger phosphorylation. It has also been
shown that the G3 domain of agrin is very plastic, meaning it can discriminate
between binding partners for a better fit.[16]

Heparan sulfate glycosaminoglycans covalently linked to the agrin protein have been
shown to play a role in the clustering of AChR. Interference in the correct
formation of heparan sulfate through the addition of chlorate to skeletal muscle
cell culture results in a decrease in the frequency of spontaneous acetylcholine
receptor (AChR) clustering. It may be that rather than solely binding directly to
the agrin protein core a number of components of the secondary scaffold may also
interact with its heparan sulfate side-chains.[17]

A role in the retention of anionic macromolecules within the vasculature has also
been suggested for agrin-linked HS at the glomerular or alveolar basement membrane.