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Mol Cell. 2010 Jul 9;39(1):100-9. doi: 10.1016/j.molcel.2010.06.007.

The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.

Author information

1
Structural Biology Program, Kimmel Center for Biology and Medicine of the Skirball Institute and Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA.

Abstract

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.

PMID:
20603078
PMCID:
PMC2917201
DOI:
10.1016/j.molcel.2010.06.007
[Indexed for MEDLINE]
Free PMC Article

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