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, 3].

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 [4].

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 [5].

References

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