Type 4B celluar metabolism function research - from Germany

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Abstract from Curr Biol 2003 Mar 18;13(6):504-9

Phosphatidylinositol-5-phosphate activation and conserved substrate

specificity of the myotubularin phosphatidylinositol 3-phosphatases.

Schaletzky J, Dove SK, Short B, Lorenzo O, Clague MJ, Barr FA.

Department of Cell Biology, Max-Planck-Institute of Biochemistry, Am

Klopferspitz 18a, 82152, sried, Germany

Phosphoinositides control many different processes required for normal

cellular function. Myotubularins are a family of Phosphatidylinositol

3-phosphate (PtdIns3P) phosphatases identified by the positional cloning

of the MTM1 gene in patients suffering from X-linked myotubular myopathy

and the MTMR2 gene in patients suffering from the demyelinating

neuropathy Charcot-Marie-Tooth disease type 4B. MTM1 is a

phosphatidylinositol phosphatase with reported specificity toward

PtdIns3P, while the related proteins MTMR2 and MTMR3 hydrolyze both

PtdIns3P and PtdIns(3,5)P2. We have investigated MTM1 and MTMR6 and find

that they use PtdIns(3,5)P2 in addition to PtdIns3P as a substrate in

vitro. The product of PtdIns(3,5)P2 hydrolysis, PtdIns5P, causes MTM1 to

form a heptameric ring that is 12.5 nm in diameter, and it is a specific

allosteric activator of MTM1, MTMR3, and MTMR6. A disease-causing

mutation at arginine 69 of MTM1 falling within a putative pleckstrin

homology domain reduces the ability of the enzyme to respond to

PtdIns5P. We propose that the myotubularin family of enzymes utilize

both PtdIns3P and PtdIns(3,5)P2 as substrates, and that PtdIns5P

functions in a positive feedback loop controlling their activity. These

findings highlight the importance of regulated phosphatase activity for

the control of phosphoinositide metabolism.