Structural insights into the regulation of human serine palmitoyltransferase complexes.

Affiliation

Wang Y(1), Niu Y(2), Zhang Z(3), Gable K(4), Gupta SD(4), Somashekarappa N(4), Han G(4), Zhao H(5), Myasnikov AG(1), Kalathur RC(1), Dunn TM(4), Lee CH(6).
Author information:
(1)Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
(2)Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
(3)State Key Laboratory of Membrane Biology, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.
(4)Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
(5)Laboratory of Membrane Biology and Biophysics, The Rockefeller University, Howard Hughes Medical Institute, New York, NY, USA.
(6)Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. [Email]

Abstract

Sphingolipids are essential lipids in eukaryotic membranes. In humans, the first and rate-limiting step of sphingolipid synthesis is catalyzed by the serine palmitoyltransferase holocomplex, which consists of catalytic components (SPTLC1 and SPTLC2) and regulatory components (ssSPTa and ORMDL3). However, the assembly, substrate processing and regulation of the complex are unclear. Here, we present 8 cryo-electron microscopy structures of the human serine palmitoyltransferase holocomplex in various functional states at resolutions of 2.6-3.4 Å. The structures reveal not only how catalytic components recognize the substrate, but also how regulatory components modulate the substrate-binding tunnel to control enzyme activity: ssSPTa engages SPTLC2 and shapes the tunnel to determine substrate specificity. ORMDL3 blocks the tunnel and competes with substrate binding through its amino terminus. These findings provide mechanistic insights into sphingolipid biogenesis governed by the serine palmitoyltransferase complex.