1zsq

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Crystal Structure of MTMR2 in complex with phosphatidylinositol 3-phosphate

Structural highlights

1zsq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.82Å
Ligands:EDO, PIB
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Myotubularins, 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.

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See Also

References

  1. ↑ Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000 May;25(1):17-9. PMID:10802647 doi:10.1038/75542
  2. ↑ Nelis E, Erdem S, Tan E, Lofgren A, Ceuterick C, De Jonghe P, Van Broeckhoven C, Timmerman V, Topaloglu H. 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 Nov;12(9):869-73. PMID:12398840
  3. ↑ Kim SA, Vacratsis PO, Firestein R, Cleary ML, Dixon JE. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4492-7. Epub 2003 Mar 31. PMID:12668758 doi:10.1073/pnas.0431052100
  4. ↑ Franklin NE, Taylor GS, Vacratsis PO. Endosomal targeting of the phosphoinositide 3-phosphatase MTMR2 is regulated by an N-terminal phosphorylation site. J Biol Chem. 2011 May 6;286(18):15841-53. doi: 10.1074/jbc.M110.209122. Epub 2011, Mar 3. PMID:21372139 doi:10.1074/jbc.M110.209122
  5. ↑ Begley MJ, Taylor GS, Brock MA, Ghosh P, Woods VL, Dixon JE. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):927-32. Epub 2006 Jan 12. PMID:16410353

Contents


PDB ID 1zsq

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