Site specific cleavage mediated by MMPs regulates function of agrin

Agrin is the key inducer of postsynaptic differentiations at the neuromuscular junction. The multidomain heparan sulfate proteoglycan is mediating via its N-terminal segment the interaction with laminin, whereas the C-terminal portion is responsible for Dystroglycan binding and clustering of the Ace...

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Bibliographic Details
Published in:PloS one 2012-09, Vol.7 (9), p.e43669-e43669
Main Authors: Patel, Trushar R, Butler, Georgina, McFarlane, Ainsley, Xie, Irene, Overall, Christopher M, Stetefeld, Jörg
Format: Article
Language:English
Subjects:
Agrin
Agrin - metabolism
Binding
Biology
Cleavage
Clustering
Complex formation
Dystroglycan
Extracellular matrix
HEK293 Cells
Humans
Laminin
Laminin - metabolism
Localization
Matrix metalloproteinases
Matrix Metalloproteinases - metabolism
Medicine
Models, Molecular
Nervous system
Protein Binding
Proteins
Receptor density
Signaling
Subfragments
Substrate Specificity
Sulfate
Sulfates
Vascular endothelial growth factor
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Summary:Agrin is the key inducer of postsynaptic differentiations at the neuromuscular junction. The multidomain heparan sulfate proteoglycan is mediating via its N-terminal segment the interaction with laminin, whereas the C-terminal portion is responsible for Dystroglycan binding and clustering of the Acetylcholine receptor. Matrix metalloproteinases (MMP) are known to play essential roles in matrix remodeling, degradation and regulation of extracellular signaling networks. Site-specific processing of Agrin provides key insight into regulatory effects of Matrix metalloproteinases (MMPs). Here, we present a detailed study of agrin processing by different MMPs together with a molecular understanding of binding and cleavage at both terminal fragments. The data suggest for a regulatory effect of MMP cleavage at particularly important functional sites of agrin. Cleave of agrin abolishes the agrin-laminin complex formation and the Acetylcholine receptor clustering at the neuromuscular junction. Agrin is a target of specific MMP processing resulting in agrin subfragments with different regulatory activities. MMP processing is a powerful tool to regulate extracellular signaling networks.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0043669