3ML4

Crystal structure of a complex between Dok7 PH-PTB and the MuSK juxtamembrane region

Summary for 3ML4

• Entry DOI: 10.2210/pdb3ml4/pdb
• Descriptor: Protein Dok-7, Muscle, skeletal receptor tyrosine-protein kinase (3 entities in total)
• Functional Keywords: tyrosine phosphorylation, adapter protein, dimerization, signaling protein
• Biological source: Mus musculus (mouse); More
• Cellular location: Cell membrane; Peripheral membrane protein: Q18PE0; Membrane; Single-pass type I membrane protein (Potential): Q61006
• Total number of polymer chains: 8
• Total formula weight: 107416.77

Authors

Bergamin, E.,Hubbard, S.R. (deposition date: 2010-04-16, release date: 2010-07-14, Last modification date: 2024-11-20)

Primary citation

Bergamin, E.,Hallock, P.T.,Burden, S.J.,Hubbard, S.R.
The Cytoplasmic Adaptor Protein Dok7 Activates the Receptor Tyrosine Kinase MuSK via Dimerization.
Mol.Cell, 39:100-109, 2010

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.

PubMed: 20603078
DOI: 10.1016/j.molcel.2010.06.007

Experimental method

X-RAY DIFFRACTION (2.6 Å)