title: Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome.
abstract: Myotubularin-related proteins are a large subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in members of the myotubularin family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. The crystal structure of a representative member of this family, MTMR2, reveals a phosphatase domain that is structurally unique among PTPs. A series of mutants are described that exhibit altered enzymatic activity and provide insight into the specificity of myotubularin phosphatases toward phosphoinositide substrates. The structure also reveals that the GRAM domain, found in myotubularin family phosphatases and predicted to occur in approximately 180 proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold. Finally, the MTMR2 structure will serve as a model for other members of the myotubularin family and provide a framework for understanding the mechanism whereby mutations in these proteins lead to disease.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Begley
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Taylor
authors.forename: Soo-A
authors.initials: SA
authors.lastname: Kim
authors.forename: Donna M
authors.initials: DM
authors.lastname: Veine
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D016415:Sequence Alignment
chemical_list: D015544:Inositol 1,4,5-Trisphosphate; C408986:MTMR2 protein, human; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor