PMID- 21969364 OWN - NLM STAT- MEDLINE DCOM- 20120116 LR - 20211020 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 286 IP - 47 DP - 2011 Nov 25 TI - Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK). PG - 40624-30 LID - 10.1074/jbc.M111.279307 [doi] AB - Neuromuscular synapse formation depends upon coordinated interactions between motor neurons and muscle fibers, leading to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. Synapse formation begins as motor axons approach muscles that are prepatterned in the prospective synaptic region in a manner that depends upon Lrp4, a member of the LDL receptor family, and muscle-specific kinase (MuSK), a receptor tyrosine kinase. Motor axons supply Agrin, which binds Lrp4 and stimulates further MuSK phosphorylation, stabilizing nascent synapses. How Agrin binds Lrp4 and stimulates MuSK kinase activity is poorly understood. Here, we demonstrate that Agrin binds to the N-terminal region of Lrp4, including a subset of the LDLa repeats and the first of four beta-propeller domains, which promotes association between Lrp4 and MuSK and stimulates MuSK kinase activity. In addition, we show that Agrin stimulates the formation of a functional complex between Lrp4 and MuSK on the surface of myotubes in the absence of the transmembrane and intracellular domains of Lrp4. Further, we demonstrate that the first Ig-like domain in MuSK, which shares homology with the NGF-binding region in Tropomyosin Receptor Kinase (TrKA), is required for MuSK to bind Lrp4. These findings suggest that Lrp4 is a cis-acting ligand for MuSK, whereas Agrin functions as an allosteric and paracrine regulator to promote association between Lrp4 and MuSK. FAU - Zhang, Wei AU - Zhang W AD - Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA. FAU - Coldefy, Anne-Sophie AU - Coldefy AS FAU - Hubbard, Stevan R AU - Hubbard SR FAU - Burden, Steven J AU - Burden SJ LA - eng GR - R37 NS036193/NS/NINDS NIH HHS/United States GR - NS53414/NS/NINDS NIH HHS/United States GR - NS36193/NS/NINDS NIH HHS/United States GR - R01 NS036193/NS/NINDS NIH HHS/United States GR - R01 NS053414/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20111003 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Agrin) RN - 0 (Immunoglobulins) RN - 0 (LDL-Receptor Related Proteins) RN - 0 (LRP4 protein, human) RN - 0 (Receptors, Cholinergic) RN - 0 (Solvents) RN - EC 2.7.10.1 (MUSK protein, human) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Agrin/*metabolism/*pharmacology MH - Animals MH - Cell Line MH - Enzyme Activation/drug effects MH - Extracellular Space/metabolism MH - Humans MH - Immunoglobulins/*chemistry MH - LDL-Receptor Related Proteins/*chemistry/*metabolism MH - Models, Molecular MH - Protein Binding/drug effects MH - Protein Structure, Tertiary MH - Receptor Protein-Tyrosine Kinases/*chemistry/*metabolism MH - Receptors, Cholinergic/*chemistry/*metabolism MH - Repetitive Sequences, Amino Acid MH - Solvents/chemistry PMC - PMC3220470 EDAT- 2011/10/05 06:00 MHDA- 2012/01/17 06:00 PMCR- 2012/11/25 CRDT- 2011/10/05 06:00 PHST- 2011/10/05 06:00 [entrez] PHST- 2011/10/05 06:00 [pubmed] PHST- 2012/01/17 06:00 [medline] PHST- 2012/11/25 00:00 [pmc-release] AID - S0021-9258(20)50413-4 [pii] AID - M111.279307 [pii] AID - 10.1074/jbc.M111.279307 [doi] PST - ppublish SO - J Biol Chem. 2011 Nov 25;286(47):40624-30. doi: 10.1074/jbc.M111.279307. Epub 2011 Oct 3.