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From Proteopedia
Crystal Structure of MTMR2 in complex with phosphatidylinositol 3-phosphate
Structural highlights
Disease[MTMR2_HUMAN] Defects in MTMR2 are the cause of Charcot-Marie-Tooth disease type 4B1 (CMT4B1) [MIM:601382]. CMT4B1 is a recessive, severe form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathy and primary peripheral axonal neuropathy. Demyelinating CMT neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4.[1] [2] Function[MTMR2_HUMAN] Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate.[3] [4] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMyotubularins, a large family of catalytically active and inactive proteins, belong to a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as physiological substrates. Here, by integrating crystallographic and deuterium-exchange mass spectrometry studies of human myotubularin-related protein-2 (MTMR2) in complex with phosphoinositides, we define the molecular basis for this unique substrate specificity. Phosphoinositide substrates bind in a pocket located on a positively charged face of the protein, suggesting an electrostatic mechanism for membrane targeting. A flexible, hydrophobic helix makes extensive interactions with the diacylglycerol moieties of substrates, explaining the specificity for membrane-bound phosphoinositides. An extensive H-bonding network and charge-charge interactions within the active site pocket determine phosphoinositide headgroup specificity. The conservation of these specificity determinants within the active, but not the inactive, myotubularins provides insight into the functional differences between the active and inactive members. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.,Begley MJ, Taylor GS, Brock MA, Ghosh P, Woods VL, Dixon JE Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):927-32. Epub 2006 Jan 12. PMID:16410353[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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