Membrane Association of Myotubularin-related Protein 2 is Mediated by a Pleckstrin Homology-GRAM Domain and a Coiled-coil Dimerization Module

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Oct 8

PMID 14530412

Citations 52

Authors

Philipp Berger

Christiane Schaffitzel

Imre Berger

Nenad Ban

Ueli Suter

Affiliations

Soon will be listed here.

Abstract

Mutations in the myotubularin (MTM)-related protein 2 (MTMR2) gene are responsible for the severe autosomal recessive neuropathy Charcot-Marie-Tooth disease type 4B1. MTMR2 belongs to the MTM family of dual-specific phosphatases that use phosphatidylinositol (PI) 3,5-bisphosphate [PI(3,5)P2] and PI 3-phosphate [PI(3)P] as their substrate. Because these substrates are localized in the membrane bilayer, membrane targeting of Mtmr2 is an important regulatory mechanism. In hypoosmotically stressed COS cells with increased levels of PI(3,5)P2, Mtmr2 is bound to the membrane of vacuoles formed under these conditions. Using several mutant forms of Mtmr2, we identified two domains that are necessary for membrane association: (i) A pleckstrin homology-GRAM domain; and (ii) a coiled-coil module. Protein-lipid overlay assays show that the pleckstrin homology-GRAM domain binds to PI(3,5)P2 and PI(5)P, a substrate and a product of the Mtmr2 enzyme, respectively. We also demonstrate that Mtmr2 forms a dimer and that the C-terminal coiled-coil is responsible for homodimerization, in addition to membrane association. Our data indicate that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for the correct regulation of MTMR2.

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References

Odorizzi G, Babst M, Emr S . Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem Sci. 2000; 25(5):229-35. DOI: 10.1016/s0968-0004(00)01543-7. View

Corvera S, DArrigo A, Stenmark H . Phosphoinositides in membrane traffic. Curr Opin Cell Biol. 1999; 11(4):460-5. DOI: 10.1016/S0955-0674(99)80066-0. View

Bolino A, Muglia M, Conforti F, Leguern E, Salih M, Georgiou D . Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000; 25(1):17-9. DOI: 10.1038/75542. View

Taylor G, Maehama T, Dixon J . Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A. 2000; 97(16):8910-5. PMC: 16795. DOI: 10.1073/pnas.160255697. View

Hurley J, Misra S . Signaling and subcellular targeting by membrane-binding domains. Annu Rev Biophys Biomol Struct. 2000; 29:49-79. PMC: 4781318. DOI: 10.1146/annurev.biophys.29.1.49. View

Gillooly D, Morrow I, Lindsay M, Gould R, Bryant N, Gaullier J . Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 2000; 19(17):4577-88. PMC: 302054. DOI: 10.1093/emboj/19.17.4577. View

Blondeau F, Laporte J, Bodin S, Superti-Furga G, Payrastre B, Mandel J . Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum Mol Genet. 2000; 9(15):2223-9. DOI: 10.1093/oxfordjournals.hmg.a018913. View

Houlden H, King R, Wood N, Thomas P, Reilly M . Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. Brain. 2001; 124(Pt 5):907-15. DOI: 10.1093/brain/124.5.907. View

Bolino A, Lonie L, Zimmer M, Boerkoel C, Takashima H, Monaco A . Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy. Neurogenetics. 2001; 3(2):107-9. DOI: 10.1007/s100480000101. View

10.

Walker D, Urbe S, Dove S, Tenza D, Raposo G, Clague M . Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity. Curr Biol. 2001; 11(20):1600-5. DOI: 10.1016/s0960-9822(01)00501-2. View

11.

Sbrissa D, Ikonomov O, Shisheva A . Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization. J Biol Chem. 2001; 277(8):6073-9. DOI: 10.1074/jbc.M110194200. View

12.

Dowler S, Kular G, Alessi D . Protein lipid overlay assay. Sci STKE. 2002; 2002(129):pl6. DOI: 10.1126/stke.2002.129.pl6. View

13.

Berger P, Young P, Suter U . Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics. 2002; 4(1):1-15. DOI: 10.1007/s10048-002-0130-z. View

14.

Berger P, Bonneick S, Willi S, Wymann M, Suter U . Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum Mol Genet. 2002; 11(13):1569-79. DOI: 10.1093/hmg/11.13.1569. View

15.

Laporte J, Blondeau F, Gansmuller A, Lutz Y, Vonesch J, Mandel J . The PtdIns3P phosphatase myotubularin is a cytoplasmic protein that also localizes to Rac1-inducible plasma membrane ruffles. J Cell Sci. 2002; 115(Pt 15):3105-17. DOI: 10.1242/jcs.115.15.3105. View

16.

Lebowitz J, Lewis M, Schuck P . Modern analytical ultracentrifugation in protein science: a tutorial review. Protein Sci. 2002; 11(9):2067-79. PMC: 2373601. DOI: 10.1110/ps.0207702. View

17.

Nelis E, Erdem S, Tan E, Lofgren A, Ceuterick C, De Jonghe P . A novel homozygous missense mutation in the myotubularin-related protein 2 gene associated with recessive Charcot-Marie-Tooth disease with irregularly folded myelin sheaths. Neuromuscul Disord. 2002; 12(9):869-73. DOI: 10.1016/s0960-8966(02)00046-9. View

18.

Sbrissa D, Ikonomov O, Deeb R, Shisheva A . Phosphatidylinositol 5-phosphate biosynthesis is linked to PIKfyve and is involved in osmotic response pathway in mammalian cells. J Biol Chem. 2002; 277(49):47276-84. DOI: 10.1074/jbc.M207576200. View

19.

Wishart M, Dixon J . PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol. 2002; 12(12):579-85. DOI: 10.1016/s0962-8924(02)02412-1. View

20.

Senderek J, Bergmann C, Weber S, Ketelsen U, Schorle H, Rudnik-Schoneborn S . Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet. 2003; 12(3):349-56. DOI: 10.1093/hmg/ddg030. View