Crystal Structure of Human Myotubularin-Related Protein 1 Provides Insight into the Structural Basis of Substrate Specificity

Abstract

Myotubularin-related protein 1 (MTMR1) is a phosphatase that belongs to the tyrosine/dual-specificity phosphatase superfamily. MTMR1 has been shown to use phosphatidylinositol 3-monophosphate (PI(3)P) and/or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) as substrates. Here, we determined the crystal structure of human MTMR1. The refined model consists of the Pleckstrin homology (PH)-GRAM and phosphatase (PTP) domains. The overall structure was highly similar to the previously reported MTMR2 structure. Interestingly, two phosphate molecules were coordinated by strictly conserved residues located in the C(X)5R motif of the active site. Additionally, our biochemical studies confirmed the substrate specificity of MTMR1 for PI(3)P and PI(3,5)P2 over other phosphatidylinositol phosphates. Our structural and enzymatic analyses provide insight into the catalytic mechanism and biochemical properties of MTMR1.

Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons

“…In this respect it is noteworthy that our interactomics screen ( Narayanan et al, 2016 ) identified two additional Mtmr family members: Mtmr1 and Mtmr5. Mtmr1 was shown to be similar to Mtmr2 in structure and substrate specificity ( Bong et al, 2016 ), but is much less studied than Mtmr2. Mtmr5 is a catalytically inactive phosphatase which binds to Mtmr2, increases its enzymatic activity and controls its subcellular localization ( Kim et al, 2003 ).…”

WANTED – Dead or alive: Myotubularins, a large disease-associated protein family

“…Between 2003 and 2016, the crystal structures of 4 active myotubularins have been determined: MTMR1 (PDB: 5C16), MTMR2 (1LW3, 1ZVR, 1M7R and 1ZSQ), MTMR6 (2YFO) and MTMR8 (4YZI) (Begley et al, 2003(Begley et al, , 2006Bong et al, 2016). A crystal structure of mouse MTMR5 has also be resolved, but only contains the C-terminal PH domain (1V5U).…”

“…A crystal structure of mouse MTMR5 has also be resolved, but only contains the C-terminal PH domain (1V5U). No major differences have been described between the 4 structures, except for the orientation of the MTMR6 PH-GRAM domain; this could impact MTMR6 oligomerization properties (Bong et al, 2016). From a 3D point of view, myotubularins are globular proteins with two main parts: the PH-GRAM domain and the catalytic domain, connected by a linker (Fig.…”

Three novel MTM1 pathogenic variants identified in Japanese patients with X‐linked myotubular myopathy

“…(c) The variant sites in XLMTM on predicted steric structure of myotubularin protein based on the crystal structure of MTMR1. The crystal structure was obtained from Bong et al (). The variant sites (Gln176, Pro199, and Trp230) and those of previously reported are indicated in red and blue, respectively…”

“…(c) The variant sites in XLMTM on predicted steric structure of myotubularin protein based on the crystal structure of MTMR1. The crystal structure was obtained from Bong et al (2016). The variant sites (Gln176, Pro199, and Trp230) and those of previously reported are indicated in red and blue, respectively participate to form substrate binding pocket, while residues at mutation sites in the second cluster at 179-241 serve a solvent-accessible/surface-exposure region outside of minimal structural core of PTP domain.…”