Mechanism of sphingolipid homeostasis revealed by structural analysis of Arabidopsis SPT-ORM1 complex

Authors

Peng Liu, Southern University of Science and Technology
Tian Xie, Southern University of Science and Technology
Xinyue Wu, Southern University of Science and Technology
Gongshe Han, Uniformed Services University of the Health Sciences
Sita D. Gupta, Uniformed Services University of the Health Sciences
Zike Zhang, Southern University of Science and Technology
Jian Yue, Southern University of Science and Technology
Feitong Dong, Southern University of Science and Technology
Kenneth Gable, Uniformed Services University of the Health Sciences
Somashekarappa Niranjanakumari, Uniformed Services University of the Health Sciences
Wanyuan Li, Hunan University
Lin Wang, Hunan University
Wenchen Liu, Southern University of Science and Technology
Ruifeng Yao, Hunan University
Edgar B. Cahoon, University of Nebraska-LincolnFollow
Teresa M. Dunn, Uniformed Services University of the Health Sciences
Xin Gong, Southern University of Science and Technology

Document Type

Article

Date of this Version

3-29-2023

Citation

Liu et al., Sci. Adv. 9, eadg0728 (2023). 10.1126/sciadv.adg0728

Comments

No claim to original U.S. Government Works.

Abstract

The serine palmitoyltransferase (SPT) complex catalyzes the first and rate-limiting step in sphingolipid biosynthesis in all eukaryotes. ORM/ORMDL proteins are negative regulators of SPT that respond to cellular sphingolipid levels. However, the molecular basis underlying ORM/ORMDL-dependent homeostatic regulation of SPT is not well understood.We determined the cryo–electron microscopy structure of Arabidopsis SPT-ORM1 complex, composed of LCB1, LCB2a, SPTssa, and ORM1, in an inhibited state. A ceramide molecule is sandwiched between ORM1 and LCB2a in the cytosolic membrane leaflet. Ceramide binding is critical for the ORM1-dependent SPT repression, and dihydroceramides and phytoceramides differentially affect this repression. A hybrid β sheet, formed by the amino termini of ORM1 and LCB2a and induced by ceramide binding, stabilizes the amino terminus of ORM1 in an inhibitory conformation. Our findings provide mechanistic insights into sphingolipid homeostatic regulation via the binding of ceramide to the SPT-ORM/ORMDL complex that may have implications for plant-specific processes such as the hypersensitive response for microbial pathogen resistance.