| Structural highlights
Function
[AGRIN_RAT] 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. 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 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. 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.[1] [2] [3] [4] [5] [6] [7] [8] Isoform 1, isoform 4, isoform 5 and isoform 6: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.[9] [10] [11] [12] [13] [14] [15] [16] Agrin N-terminal 110 kDa subunit: is 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).[17] [18] [19] [20] [21] [22] [23] [24] Agrin C-terminal 22 kDa fragment: 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.[25] [26] [27] [28] [29] [30] [31] [32] [LRP4_RAT] Mediates SOST-dependent inhibition of bone formation (By similarity). Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling (By similarity). Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN-induced phosphorylation of MUSK, the kinase of the complex. 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. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes.
Publication Abstract from PubMed
Synapses are the fundamental units of neural circuits that enable complex behaviors. The neuromuscular junction (NMJ), a synapse formed between a motoneuron and a muscle fiber, has contributed greatly to understanding of the general principles of synaptogenesis as well as of neuromuscular disorders. NMJ formation requires neural agrin, a motoneuron-derived protein, which interacts with LRP4 (low-density lipoprotein receptor-related protein 4) to activate the receptor tyrosine kinase MuSK (muscle-specific kinase). However, little is known of how signals are transduced from agrin to MuSK. Here, we present the first crystal structure of an agrin-LRP4 complex, consisting of two agrin-LRP4 heterodimers. Formation of the initial binary complex requires the z8 loop that is specifically present in neuronal, but not muscle, agrin and that promotes the synergistic formation of the tetramer through two additional interfaces. We show that the tetrameric complex is essential for neuronal agrin-induced acetylcholine receptor (AChR) clustering. Collectively, these results provide new insight into the agrin-LRP4-MuSK signaling cascade and NMJ formation and represent a novel mechanism for activation of receptor tyrosine kinases.
Structural basis of agrin-LRP4-MuSK signaling.,Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, Jin R Genes Dev. 2012 Feb 1;26(3):247-58. doi: 10.1101/gad.180885.111. PMID:22302937[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ferns MJ, Campanelli JT, Hoch W, Scheller RH, Hall Z. The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron. 1993 Sep;11(3):491-502. PMID:8398142
- ↑ 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
- ↑ O'Toole JJ, Deyst KA, Bowe MA, Nastuk MA, McKechnie BA, Fallon JR. Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7369-74. PMID:8693000
- ↑ Kim ML, Chandrasekharan K, Glass M, Shi S, Stahl MC, Kaspar B, Stanley P, Martin PT. O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci. 2008 Nov;39(3):452-64. doi: 10.1016/j.mcn.2008.07.026. Epub, 2008 Aug 15. PMID:18775496 doi:http://dx.doi.org/10.1016/j.mcn.2008.07.026
- ↑ McCroskery S, Bailey A, Lin L, Daniels MP. Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures. Neuroscience. 2009 Sep 29;163(1):168-79. doi: 10.1016/j.neuroscience.2009.06.012., Epub 2009 Jun 10. PMID:19524020 doi:http://dx.doi.org/10.1016/j.neuroscience.2009.06.012
- ↑ Lin L, McCroskery S, Ross JM, Chak Y, Neuhuber B, Daniels MP. Induction of filopodia-like protrusions by transmembrane agrin: role of agrin glycosaminoglycan chains and Rho-family GTPases. Exp Cell Res. 2010 Aug 15;316(14):2260-77. doi: 10.1016/j.yexcr.2010.05.006. Epub, 2010 May 13. PMID:20471381 doi:http://dx.doi.org/10.1016/j.yexcr.2010.05.006
- ↑ Tseng CN, Zhang L, Wu SL, Wang WF, Wang ZZ, Cascio M. Asparagine of z8 insert is critical for the affinity, conformation, and acetylcholine receptor-clustering activity of neural agrin. J Biol Chem. 2010 Sep 3;285(36):27641-51. doi: 10.1074/jbc.M110.130625. Epub 2010, Jun 21. PMID:20566625 doi:http://dx.doi.org/10.1074/jbc.M110.130625
- ↑ Banyai L, Sonderegger P, Patthy L. Agrin binds BMP2, BMP4 and TGFbeta1. PLoS One. 2010 May 21;5(5):e10758. doi: 10.1371/journal.pone.0010758. PMID:20505824 doi:http://dx.doi.org/10.1371/journal.pone.0010758
- ↑ Ferns MJ, Campanelli JT, Hoch W, Scheller RH, Hall Z. The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron. 1993 Sep;11(3):491-502. PMID:8398142
- ↑ 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
- ↑ O'Toole JJ, Deyst KA, Bowe MA, Nastuk MA, McKechnie BA, Fallon JR. Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7369-74. PMID:8693000
- ↑ Kim ML, Chandrasekharan K, Glass M, Shi S, Stahl MC, Kaspar B, Stanley P, Martin PT. O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci. 2008 Nov;39(3):452-64. doi: 10.1016/j.mcn.2008.07.026. Epub, 2008 Aug 15. PMID:18775496 doi:http://dx.doi.org/10.1016/j.mcn.2008.07.026
- ↑ McCroskery S, Bailey A, Lin L, Daniels MP. Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures. Neuroscience. 2009 Sep 29;163(1):168-79. doi: 10.1016/j.neuroscience.2009.06.012., Epub 2009 Jun 10. PMID:19524020 doi:http://dx.doi.org/10.1016/j.neuroscience.2009.06.012
- ↑ Lin L, McCroskery S, Ross JM, Chak Y, Neuhuber B, Daniels MP. Induction of filopodia-like protrusions by transmembrane agrin: role of agrin glycosaminoglycan chains and Rho-family GTPases. Exp Cell Res. 2010 Aug 15;316(14):2260-77. doi: 10.1016/j.yexcr.2010.05.006. Epub, 2010 May 13. PMID:20471381 doi:http://dx.doi.org/10.1016/j.yexcr.2010.05.006
- ↑ Tseng CN, Zhang L, Wu SL, Wang WF, Wang ZZ, Cascio M. Asparagine of z8 insert is critical for the affinity, conformation, and acetylcholine receptor-clustering activity of neural agrin. J Biol Chem. 2010 Sep 3;285(36):27641-51. doi: 10.1074/jbc.M110.130625. Epub 2010, Jun 21. PMID:20566625 doi:http://dx.doi.org/10.1074/jbc.M110.130625
- ↑ Banyai L, Sonderegger P, Patthy L. Agrin binds BMP2, BMP4 and TGFbeta1. PLoS One. 2010 May 21;5(5):e10758. doi: 10.1371/journal.pone.0010758. PMID:20505824 doi:http://dx.doi.org/10.1371/journal.pone.0010758
- ↑ Ferns MJ, Campanelli JT, Hoch W, Scheller RH, Hall Z. The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron. 1993 Sep;11(3):491-502. PMID:8398142
- ↑ 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
- ↑ O'Toole JJ, Deyst KA, Bowe MA, Nastuk MA, McKechnie BA, Fallon JR. Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7369-74. PMID:8693000
- ↑ Kim ML, Chandrasekharan K, Glass M, Shi S, Stahl MC, Kaspar B, Stanley P, Martin PT. O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci. 2008 Nov;39(3):452-64. doi: 10.1016/j.mcn.2008.07.026. Epub, 2008 Aug 15. PMID:18775496 doi:http://dx.doi.org/10.1016/j.mcn.2008.07.026
- ↑ McCroskery S, Bailey A, Lin L, Daniels MP. Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures. Neuroscience. 2009 Sep 29;163(1):168-79. doi: 10.1016/j.neuroscience.2009.06.012., Epub 2009 Jun 10. PMID:19524020 doi:http://dx.doi.org/10.1016/j.neuroscience.2009.06.012
- ↑ Lin L, McCroskery S, Ross JM, Chak Y, Neuhuber B, Daniels MP. Induction of filopodia-like protrusions by transmembrane agrin: role of agrin glycosaminoglycan chains and Rho-family GTPases. Exp Cell Res. 2010 Aug 15;316(14):2260-77. doi: 10.1016/j.yexcr.2010.05.006. Epub, 2010 May 13. PMID:20471381 doi:http://dx.doi.org/10.1016/j.yexcr.2010.05.006
- ↑ Tseng CN, Zhang L, Wu SL, Wang WF, Wang ZZ, Cascio M. Asparagine of z8 insert is critical for the affinity, conformation, and acetylcholine receptor-clustering activity of neural agrin. J Biol Chem. 2010 Sep 3;285(36):27641-51. doi: 10.1074/jbc.M110.130625. Epub 2010, Jun 21. PMID:20566625 doi:http://dx.doi.org/10.1074/jbc.M110.130625
- ↑ Banyai L, Sonderegger P, Patthy L. Agrin binds BMP2, BMP4 and TGFbeta1. PLoS One. 2010 May 21;5(5):e10758. doi: 10.1371/journal.pone.0010758. PMID:20505824 doi:http://dx.doi.org/10.1371/journal.pone.0010758
- ↑ Ferns MJ, Campanelli JT, Hoch W, Scheller RH, Hall Z. The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. Neuron. 1993 Sep;11(3):491-502. PMID:8398142
- ↑ 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
- ↑ O'Toole JJ, Deyst KA, Bowe MA, Nastuk MA, McKechnie BA, Fallon JR. Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7369-74. PMID:8693000
- ↑ Kim ML, Chandrasekharan K, Glass M, Shi S, Stahl MC, Kaspar B, Stanley P, Martin PT. O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci. 2008 Nov;39(3):452-64. doi: 10.1016/j.mcn.2008.07.026. Epub, 2008 Aug 15. PMID:18775496 doi:http://dx.doi.org/10.1016/j.mcn.2008.07.026
- ↑ McCroskery S, Bailey A, Lin L, Daniels MP. Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures. Neuroscience. 2009 Sep 29;163(1):168-79. doi: 10.1016/j.neuroscience.2009.06.012., Epub 2009 Jun 10. PMID:19524020 doi:http://dx.doi.org/10.1016/j.neuroscience.2009.06.012
- ↑ Lin L, McCroskery S, Ross JM, Chak Y, Neuhuber B, Daniels MP. Induction of filopodia-like protrusions by transmembrane agrin: role of agrin glycosaminoglycan chains and Rho-family GTPases. Exp Cell Res. 2010 Aug 15;316(14):2260-77. doi: 10.1016/j.yexcr.2010.05.006. Epub, 2010 May 13. PMID:20471381 doi:http://dx.doi.org/10.1016/j.yexcr.2010.05.006
- ↑ Tseng CN, Zhang L, Wu SL, Wang WF, Wang ZZ, Cascio M. Asparagine of z8 insert is critical for the affinity, conformation, and acetylcholine receptor-clustering activity of neural agrin. J Biol Chem. 2010 Sep 3;285(36):27641-51. doi: 10.1074/jbc.M110.130625. Epub 2010, Jun 21. PMID:20566625 doi:http://dx.doi.org/10.1074/jbc.M110.130625
- ↑ Banyai L, Sonderegger P, Patthy L. Agrin binds BMP2, BMP4 and TGFbeta1. PLoS One. 2010 May 21;5(5):e10758. doi: 10.1371/journal.pone.0010758. PMID:20505824 doi:http://dx.doi.org/10.1371/journal.pone.0010758
- ↑ Zong Y, Zhang B, Gu S, Lee K, Zhou J, Yao G, Figueiredo D, Perry K, Mei L, Jin R. Structural basis of agrin-LRP4-MuSK signaling. Genes Dev. 2012 Feb 1;26(3):247-58. doi: 10.1101/gad.180885.111. PMID:22302937 doi:10.1101/gad.180885.111
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