| Structural highlights
Function
AGRIN_CHICK Isoform 1: 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. 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 funtion in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homestasis 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.[1] [2] [3] [4] [5] [6] [7] Isoform 9: transmembrane agrin (TM-agrin), the predominant 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.[8] [9] [10] [11] [12] [13] [14] Isoform 2, isoform 4 and isoform 7: muscle agrin isoforms, which lack the 8-amino acid insert at the 'B' site, but with the insert at the'A' site have no AChr clustering activity nor MUSK activation but bind heparin. Bind alpha-dystroglycan with lower affinity.[15] [16] [17] [18] [19] [20] [21] Isoform 5: muscle agrin A0B0 lacking inserts at both 'A' and 'B' sites has no heparin-binding nor AChR clustering activity but binds strongly alpha-dystroglycan.[22] [23] [24] [25] [26] [27] [28] Agrin N-terminal 110 kDa subunit: is involved in modulation of growth factor signaling (By similarity). Involved also in the 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.[29] [30] [31] [32] [33] [34] [35] Agrin C-terminal 22 kDa fragment: this released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'B' splice variants of this fragment also show an increase in the number of filopodia.[36] [37] [38] [39] [40] [41] [42]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Agrin is a multidomain heparan sulfate proteoglycan involved in postsynaptic differentiation at the neuromuscular junction. Binding of agrin to synaptic basal lamina is mediated by the N-terminal agrin (NtA) domain. The NtA domain of agrin is followed by a tandem of nine follistatin-like (FS) domains forming a rod-like spacer to the laminin G-like domains of the molecule. Here we report that the most C-terminal cysteine residue of NtA (Cys123) forms an interdomain disulfide bond with the FOLN subdomain of the FS module. Remarkably, this single cysteine is flanked by Leu117 and Val124, which are two essential beta-branched amino acids forming the heterocomplex of NtA with the gamma 1 chain of laminin. Moreover, we show that this covalent linkage compensates for the seven amino acid residue splice insert at the very C-terminal helix H3 and causes a rigid interface between NtA and FS independent of the alternative mRNA splice event. These results suggest that the interdomain disulfide bond between the NtA and the first FS domain might be important for the proper folding of agrin.
An interdomain disulfide bridge links the NtA and first FS domain in agrin.,McFarlane AA, Stetefeld J Protein Sci. 2009 Dec;18(12):2421-8. PMID:19845005[43]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ Gesemann M, Denzer AJ, Ruegg MA. Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site. J Cell Biol. 1995 Feb;128(4):625-36. PMID:7860635
- ↑ Bezakova G, Helm JP, Francolini M, Lomo T. Effects of purified recombinant neural and muscle agrin on skeletal muscle fibers in vivo. J Cell Biol. 2001 Jun 25;153(7):1441-52. PMID:11425874
- ↑ Baerwald-de la Torre K, Winzen U, Halfter W, Bixby JL. Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J Neurochem. 2004 Jul;90(1):50-61. PMID:15198666 doi:http://dx.doi.org/10.1111/j.1471-4159.2004.02454.x
- ↑ Scotton P, Bleckmann D, Stebler M, Sciandra F, Brancaccio A, Meier T, Stetefeld J, Ruegg MA. Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J Biol Chem. 2006 Dec 1;281(48):36835-45. Epub 2006 Sep 29. PMID:17012237 doi:http://dx.doi.org/10.1074/jbc.M607887200
- ↑ Sallum CO, Kammerer RA, Alexandrescu AT. Thermodynamic and structural studies of carbohydrate binding by the agrin-G3 domain. Biochemistry. 2007 Aug 21;46(33):9541-50. Epub 2007 Jul 25. PMID:17649979 doi:http://dx.doi.org/10.1021/bi7006383
- ↑ Porten E, Seliger B, Schneider VA, Woll S, Stangel D, Ramseger R, Kroger S. The process-inducing activity of transmembrane agrin requires follistatin-like domains. J Biol Chem. 2010 Jan 29;285(5):3114-25. doi: 10.1074/jbc.M109.039420. Epub 2009 , Nov 25. PMID:19940118 doi:http://dx.doi.org/10.1074/jbc.M109.039420
- ↑ Patel TR, Butler G, McFarlane A, Xie I, Overall CM, Stetefeld J. Site specific cleavage mediated by MMPs regulates function of agrin. PLoS One. 2012;7(9):e43669. doi: 10.1371/journal.pone.0043669. Epub 2012 Sep 11. PMID:22984437 doi:http://dx.doi.org/10.1371/journal.pone.0043669
- ↑ McFarlane AA, Stetefeld J. An interdomain disulfide bridge links the NtA and first FS domain in agrin. Protein Sci. 2009 Dec;18(12):2421-8. PMID:19845005 doi:10.1002/pro.276
|
