The Mechanism of Membrane Targeting of Human Sphingosine Kinase 1*

  1. Wonhwa Cho,2
  1. Chemistry, University of Illinois, Chicago, Illinois 60607, the Department of Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and the §Department of Life Science, Kwangju Institute of Science and Technology, Gwang-Ju, 500-712 Korea
  1. 2 To whom correspondence should be addressed: M/C 111, 845 West Taylor St., Chicago, IL 60607-7061. Tel.: 312-996-4883; Fax: 312-996-2183; E-mail: wcho{at}uic.edu.

Abstract

Sphingosine 1-phosphate is a bioactive sphingolipid that regulates cell growth and suppresses programmed cell death. The biosynthesis of sphingosine 1-phosphate is catalyzed by sphingosine kinase (SK) but the mechanism by which the subcellular localization and activity of SK is regulated in response to various stimuli is not fully understood. To elucidate the origin and structural determinant of the specific subcellular localization of SK, we performed biophysical and cell studies of human SK1 (hSK1) and selected mutants. In vitro measurements showed that hSK1 selectively bound phosphatidylserine over other anionic phospholipids and strongly preferred the plasma membrane-mimicking membrane to other cellular membrane mimetics. Mutational analysis indicates that conserved Thr54 and Asn89 in the putative membrane-binding surface are essential for lipid selectivity and membrane targeting both in vitro and in the cell. Also, phosphorylation of Ser225 enhances the membrane affinity and plasma membrane selectivity of hSK1, presumably by modulating the interaction of Thr54 and Asn89 with the membrane. Collectively, these studies suggest that the specific plasma membrane localization and activation of SK1 is mediated largely by specific lipid-protein interactions.

  • Received July 13, 2005.
  • Revision received October 11, 2005.
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This Article

  1. The Journal of Biological Chemistry 280, 43030-43038.
  1. All Versions of this Article:
    1. M507574200v1
    2. 280/52/43030 (most recent)

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