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PDBsum entry 3ml4
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Signaling protein
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PDB id
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3ml4
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References listed in PDB file
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Key reference
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Title
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The cytoplasmic adaptor protein dok7 activates the receptor tyrosine kinase musk via dimerization.
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Authors
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E.Bergamin,
P.T.Hallock,
S.J.Burden,
S.R.Hubbard.
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Ref.
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Mol Cell, 2010,
39,
100-109.
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PubMed id
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Abstract
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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.
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