A human phospholipid phosphatase activated by a transmembrane control module

Journal of Lipid Research

Ludivine Frezza¹  Anja Feuer²  Audrey Le³  Carlos A. Villalba-Galea⁴  Daniela N. Schreiber⁴  Christian R. Halaszovich⁴  Angeliki Mavrantoni⁴  Michael G. Leitner⁴  Dominik Oliver⁵ 

[1] ;Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637;Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298;Institute of Physiology and Pathophysiology, Philipps-Universität Marburg, 35037, Marburg, Germany;To whom correspondence should be addressed.;

关键词: phosphoinositides;    voltage sensor;    electrochemical coupling;    ion channel;    lipid signaling;   

DOI  :  

来源: DOAJ

【 摘 要 】

In voltage-sensitive phosphatases (VSPs), a transmembrane voltage sensor domain (VSD) controls an intracellular phosphoinositide phosphatase domain, thereby enabling immediate initiation of intracellular signals by membrane depolarization. The existence of such a mechanism in mammals has remained elusive, despite the presence of VSP-homologous proteins in mammalian cells, in particular in sperm precursor cells. Here we demonstrate activation of a human VSP (hVSP1/TPIP) by an intramolecular switch. By engineering a chimeric hVSP1 with enhanced plasma membrane targeting containing the VSD of a prototypic invertebrate VSP, we show that hVSP1 is a phosphoinositide-5-phosphatase whose predominant substrate is PI(4,5)P2. In the chimera, enzymatic activity is controlled by membrane potential via hVSP1’s endogenous phosphoinositide binding motif. These findings suggest that the endogenous VSD of hVSP1 is a control module that initiates signaling through the phosphatase domain and indicate a role for VSP-mediated phosphoinositide signaling in mammals.

【 授权许可】

Unknown