WANTED - Dead or alive: Myotubularins, a large disease-associated protein family.
Myotubularins define a large family of proteins conserved through evolution. Several members are mutated in different neuromuscular diseases including centronuclear myopathies and Charcot-Marie-Tooth (CMT) neuropathies, or are linked to a predisposition to obesity and cancer. While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P2implicated in membrane trafficking and autophagy, and producing PtdIns5P, others lack key residues in the catalytic site and are classified as dead-phosphatases. However, these dead phosphatases regulate phosphoinositide-dependent cellular pathways by binding to catalytically active myotubularins. Here we review previous studies on the molecular regulation and physiological roles of myotubularins. We also used the recent myotubularins three-dimensional structures to underline key residues that are mutated in neuromuscular diseases and required for enzymatic activity. In addition, through database mining and analysis, expression profile and specific isoforms of the different myotubularins are described in depth, as well as a revisited protein interaction network. Comparison of the interactome and expression data for each myotubularin highlights specific protein complexes and tissues where myotubularins should have a key regulatory role.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 Rue Laurent Fries, BP10142, 67404 Illkirch, France; INSERM U964, 67404 Illkirch, France; CNRS, UMR7104, 67404 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France; Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg and CNRS, 21 Rue Descartes, 67084 Strasbourg, France. Electronic address: raess@igbmc.fr.
Matthieu A
MA
Raess
Department of Molecular and Cellular Genetics, UMR7156, Université de Strasbourg and CNRS, 21 Rue Descartes, 67084 Strasbourg, France. Electronic address: s.friant@unistra.fr.
Sylvie
S
Friant
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 Rue Laurent Fries, BP10142, 67404 Illkirch, France; INSERM U964, 67404 Illkirch, France; CNRS, UMR7104, 67404 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France. Electronic address: belinda@igbmc.fr.
Belinda S
BS
Cowling
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 Rue Laurent Fries, BP10142, 67404 Illkirch, France; INSERM U964, 67404 Illkirch, France; CNRS, UMR7104, 67404 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67404 Illkirch, France. Electronic address: jocelyn@igbmc.fr.
Jocelyn
J
Laporte
D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008958:Models, Molecular; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D018129:Phosphatidylinositol Phosphates; D020033:Protein Isoforms; D012333:RNA, Messenger; C106336:phosphatidylinositol 3,5-diphosphate; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin
Congenital myopathy; GTEx database; Myotubular myopathy; Myotubularin; Neuropathy; Sbf1