Phosphatase Subfamily MTMR5

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR5 (SBF)

MTMR5 subfamily is an inactive phosphatase (pseudophosphatase), which major function is regulating active phosphatase MTMR2 via interactions.

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

Chordate MTMR5s have a domain combination of DENN domain, PH/GRAM domain, phosphatase domain, coiled-coil domain and PH domain.

The PH/GRAM domain is similar to PH domain in structure and is found in membrane-associated proteins.

The DENN domain interacts directly with members of the Rab family of small GTPases and functions enzymatically as Rab-specific guanine nucleotide exchange factors. Human MTMR5 and MTMR13 have GEF activity toward Rab28, a poorly characterized and distant member of the Rab superfamily [1]. Fruit fly Sbf regulates Rab21, which specifies an endosomal pathway and cortical control.

Coiled-coil domain mediates the interactions of MTMR5 and MTMR13 with MTMR2, which results in the increase of enzymatic activity of MTMR2 [2, 3].

In most metazoa except chordates, an additional C1 domain is found adjacent to the C-terminal PH domain, resulting in a domain combination of DENN, GRAM, phosphatase, C1 and PH.

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.

The interaction between MTMR5 subfamily and MTMR1 subfamily is also observed in fruit fly, which indicates the conservation of the this regulatory mechanism. In addition, fruit fly Sbf has been reported as a critical coordinator of PI(3)P and Rab21 regulation, which specifies an endosomal pathway and cortical control [4],.

Diseases

Mice deficient for MTMR5 exhibit male infertility characterized by azoospermia [5].

Deleterious mutations in human MTMR13 (SBF2) causes 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 [6]. In addition, loss of Mtmr13 in mice leads to a peripheral neuropathy with many of the key features of CMT4B. It worthy pointing out that recessive mutations in either MTMR2 or MTMR13 lead to nearly indistinguishable forms of CMT4B [7]. MTMR5 mutations cause CMT4B, as well [8].

References

1. 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 |
2. 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 |
3. 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 |
4. Jean S, Cox S, Schmidt EJ, Robinson FL, and Kiger A. Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling. Mol Biol Cell. 2012 Jul;23(14):2723-40. DOI:10.1091/mbc.E12-05-0375 |
5. 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 |
6. Chen M, Wu J, Liang N, Tang L, Chen Y, Chen H, Wei W, Wei T, Huang H, Yi X, and Qi M. Identification of a novel SBF2 frameshift mutation in charcot-marie-tooth disease type 4B2 using whole-exome sequencing. Genomics Proteomics Bioinformatics. 2014 Oct;12(5):221-7. DOI:10.1016/j.gpb.2014.09.003 |
7. 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 |
8. Nakhro K, Park JM, Hong YB, Park JH, Nam SH, Yoon BR, Yoo JH, Koo H, Jung SC, Kim HL, Kim JY, Choi KG, Choi BO, and Chung KW. SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. Neurology. 2013 Jul 9;81(2):165-73. DOI:10.1212/WNL.0b013e31829a3421 |