The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.
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.
Bergamin
Elisa
E
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.
Hallock
Peter T
PT
Burden
Steven J
SJ
Hubbard
Stevan R
SR
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C511692:DOK7 protein, human; C511694:Dok-7 protein, mouse; D009124:Muscle Proteins; D010716:Phosphatidylinositols; D011950:Receptors, Cholinergic; D019000:Phosphotyrosine; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases