Phosphatase Subfamily MTMR5
Phosphatase Classification: FoldCC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR5 (SBF)
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Evolution
MTMR5 subfamily is found throughout metazoan. It consists of two members in human, MTMR5 and MTMR13, also called SBF1 and SBF2, respectively. In fruit fly and C elegans, a single copy is found.
Domain Structure
MTMR5 subfamily has a DENN domain, PH/GRAM domain, phosphatase domain, coiled-coil domain and PH domain. The GRAM domain is similar to PH domain in structure and is found in membrane-associated proteins.
DENN domains interact directly with members of the Rab family of small GTPases and that DENN domains function enzymatically as Rab-specific guanine nucleotide exchange factors. MTMR5 and MTMR13 have GEF activity toward Rab28, a poorly characterized and distant member of the Rab superfamily[1].
Coiled-coil domain mediates the interactions of MTMR5 and MTMR13 with MTMR2, which results in the increase of enzymatic activity of MTMR2 [2].
Catalytic activity and functions
MTMR5 subfamily is conservatively inactive in metazoan.
Human MTMR5 interact with MTMR2 (see MTMR1 subfamily) via its coiled-coil domain and mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization [2]. This is a good example of inactive phosphatase functions as regulator of active phosphatase.
Disease
Mice deficient for MTMR5 exhibit male infertility characterized by azoospermia [3].
loss of Mtmr13 in mice leads to a peripheral neuropathy with many of the key features of Charcot–Marie–Tooth disease type 4B (CMT4B), which is a severe, demyelinating peripheral neuropathy characterized by slowed nerve conduction velocity, axon loss, and distinctive myelin outfolding and infolding [4].
References
- Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, and Barr FA. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. J Cell Biol. 2010 Oct 18;191(2):367-81. DOI:10.1083/jcb.201008051 |
- Kim SA, Vacratsis PO, Firestein R, Cleary ML, and 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. DOI:10.1073/pnas.0431052100 |
- Firestein R, Nagy PL, Daly M, Huie P, Conti M, and Cleary ML. Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1. J Clin Invest. 2002 May;109(9):1165-72. DOI:10.1172/JCI12589 |
- Robinson FL, Niesman IR, Beiswenger KK, and Dixon JE. Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4916-21. DOI:10.1073/pnas.0800742105 |
- Robinson FL and Dixon JE. The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease. J Biol Chem. 2005 Sep 9;280(36):31699-707. DOI:10.1074/jbc.M505159200 |
