| Structural highlights
Function
[DOK7_MOUSE] Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. Induces autophosphorylation of MUSK.[1] [2] [MUSK_MOUSE] Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle. Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation.[3] [4] [5] [6] [7]
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
Formation of the vertebrate neuromuscular junction requires, among others proteins, Agrin, a neuronally derived ligand, and the following muscle proteins: LRP4, the receptor for Agrin; MuSK, a receptor tyrosine kinase (RTK); and Dok7 (or Dok-7), a cytoplasmic adaptor protein. Dok7 comprises a pleckstrin-homology (PH) domain, a phosphotyrosine-binding (PTB) domain, and C-terminal sites of tyrosine phosphorylation. Unique among adaptor proteins recruited to RTKs, Dok7 is not only a substrate of MuSK, but also an activator of MuSK's kinase activity. Here, we present the crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide representing the Dok7-binding site on MuSK. The structure and biochemical data reveal a dimeric arrangement of Dok7 PH-PTB that facilitates trans-autophosphorylation of the kinase activation loop. The structure provides the molecular basis for MuSK activation by Dok7 and for rationalizing several Dok7 loss-of-function mutations found in patients with congenital myasthenic syndromes.
The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.,Bergamin E, Hallock PT, Burden SJ, Hubbard SR Mol Cell. 2010 Jul 9;39(1):100-9. PMID:20603078[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006 Jun 23;312(5781):1802-5. PMID:16794080 doi:312/5781/1802
- ↑ Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell. 2010 Jul 9;39(1):100-9. PMID:20603078 doi:10.1016/j.molcel.2010.06.007
- ↑ DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996 May 17;85(4):501-12. PMID:8653786
- ↑ Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature. 2001 Apr 26;410(6832):1057-64. PMID:11323662 doi:http://dx.doi.org/10.1038/35074025
- ↑ Lacazette E, Le Calvez S, Gajendran N, Brenner HR. A novel pathway for MuSK to induce key genes in neuromuscular synapse formation. J Cell Biol. 2003 May 26;161(4):727-36. Epub 2003 May 19. PMID:12756238 doi:http://dx.doi.org/10.1083/jcb.200210156
- ↑ Luo ZG, Je HS, Wang Q, Yang F, Dobbins GC, Yang ZH, Xiong WC, Lu B, Mei L. Implication of geranylgeranyltransferase I in synapse formation. Neuron. 2003 Nov 13;40(4):703-17. PMID:14622576
- ↑ Mittaud P, Camilleri AA, Willmann R, Erb-Vogtli S, Burden SJ, Fuhrer C. A single pulse of agrin triggers a pathway that acts to cluster acetylcholine receptors. Mol Cell Biol. 2004 Sep;24(18):7841-54. PMID:15340048 doi:http://dx.doi.org/10.1128/MCB.24.18.7841-7854.2004
- ↑ Bergamin E, Hallock PT, Burden SJ, Hubbard SR. The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Mol Cell. 2010 Jul 9;39(1):100-9. PMID:20603078 doi:10.1016/j.molcel.2010.06.007
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