Department of Pharmacology, University of California, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11860-5. doi: 10.1073/pnas.1109290108. Epub 2011 Jul 5.
PTPMT1 (PTP localized to the Mitochondrion 1) is a member of the protein tyrosine phosphatase superfamily that is localized exclusively to the mitochondrion. We recently reported that PTPMT1 dephosphorylates phosphatidylglycerol phosphate, an essential intermediate of cardiolipin biosynthesis. To gain further insights into the molecular basis of PTPMT1 function, we determined the crystal structures of the phosphatase domain of PTPMT1. PTPMT1 exhibits a canonical protein tyrosine phosphatase domain fold, resembling many dual-specificity phosphatases such as phosphatase and tensin homolog and vaccinia H1-related phosphatase. We also determined the structure of the catalytically inactive phosphatase in complex with a surrogate substrate, phosphatidylinositol 5-phosphate, which sheds light on the substrate recognition and specificity of PTPMT1. Comparison of the apo and substrate-bound structures of PTPMT1 suggests that it undergoes significant conformational change during catalysis, and we further demonstrated that an evolutionarily conserved EEYE loop is important for its activity.
PTPMT1（定位于线粒体 1 的蛋白酪氨酸磷酸酶 1）是蛋白酪氨酸磷酸酶超家族的成员，它专门定位于线粒体。我们最近报道 PTPMT1 去磷酸化磷脂酰甘油磷酸，这是心磷脂生物合成的必需中间产物。为了更深入地了解 PTPMT1 功能的分子基础，我们测定了 PTPMT1 的磷酸酶结构域的晶体结构。PTPMT1 表现出典型的蛋白酪氨酸磷酸酶结构域折叠，类似于许多双特异性磷酸酶，如磷酸酶和张力蛋白同源物和牛痘 H1 相关磷酸酶。我们还测定了与替代底物磷脂酰肌醇 5-磷酸结合的无活性磷酸酶的结构，这揭示了 PTPMT1 的底物识别和特异性。PTPMT1 的无配体和底物结合结构的比较表明，它在催化过程中经历了显著的构象变化，我们进一步证明了进化上保守的 EEYE 环对其活性很重要。
