The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.
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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. doi: 10.1016/j.molcel.2010.06.007.
- PubMed ID
- 20603078 [ View in PubMed]
- 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.