3pve

Structural highlights

Function

AGRIN_MOUSE Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. This neuron-specific (z+) isoform is a component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This transmembrane agrin (TM-agrin) isoform, the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. Isoform 2 and isoform 3: these isoforms lacking the 'z' insert (z0) are muscle-specific, have no AChR clustering ability and may be involved in nervous system endothelial cell differentiation. Involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity).^{[1] [2] [3] [4] [5] [6] [7]} This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.

See Also

• Agrin 3D structures

References

1. ↑ Burgess RW, Nguyen QT, Son YJ, Lichtman JW, Sanes JR. Alternatively spliced isoforms of nerve the neuromuscular junction. Neuron. 1999 May;23(1):33-44. PMID:10402191 doi:10.1016/s0896-6273(00)80751-5
2. ↑ Burgess RW, Skarnes WC, Sanes JR. Agrin isoforms with distinct amino termini: differential expression, localization, and function. J Cell Biol. 2000 Oct 2;151(1):41-52. PMID:11018052 doi:10.1083/jcb.151.1.41
3. ↑ Hoover CL, Hilgenberg LG, Smith MA. The COOH-terminal domain of agrin signals via a synaptic receptor in central nervous system neurons. J Cell Biol. 2003 Jun 9;161(5):923-32. PMID:12796478 doi:10.1083/jcb.200301013
4. ↑ Ksiazek I, Burkhardt C, Lin S, Seddik R, Maj M, Bezakova G, Jucker M, Arber S, Caroni P, Sanes JR, Bettler B, Ruegg MA. Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J Neurosci. 2007 Jul 4;27(27):7183-95. PMID:17611272 doi:10.1523/JNEUROSCI.1609-07.2007
5. ↑ Matsumoto-Miyai K, Sokolowska E, Zurlinden A, Gee CE, Lüscher D, Hettwer S, Wölfel J, Ladner AP, Ster J, Gerber U, Rülicke T, Kunz B, Sonderegger P. Coincident pre neurotrypsin-dependent agrin cleavage. Cell. 2009 Mar 20;136(6):1161-71. PMID:19303856 doi:10.1016/j.cell.2009.02.034
6. ↑ Bütikofer L, Zurlinden A, Bolliger MF, Kunz B, Sonderegger P. Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia. FASEB J. 2011 Dec;25(12):4378-93. PMID:21885656 doi:10.1096/fj.11-191262
7. ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD. Agrin acts via a MuSK receptor complex. Cell. 1996 May 17;85(4):513-23. PMID:8653787