Structural basis of CD97 activation and G-protein coupling

Na Wang; Yu Qian; Ruixue Xia; Xinyan Zhu; Yangjie Xiong; Anqi Zhang; Changyou Guo; Yuanzheng He

doi:10.1016/j.chembiol.2023.08.003

Structural basis of CD97 activation and G-protein coupling

Cell Chem Biol. 2023 Nov 16;30(11):1343-1353.e5. doi: 10.1016/j.chembiol.2023.08.003. Epub 2023 Sep 5.

Authors

Na Wang¹, Yu Qian¹, Ruixue Xia¹, Xinyan Zhu¹, Yangjie Xiong¹, Anqi Zhang¹, Changyou Guo¹, Yuanzheng He²

Affiliations

¹ Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
² Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China. Electronic address: ajian.he@hit.edu.cn.

PMID: 37673067
DOI: 10.1016/j.chembiol.2023.08.003

Abstract

CD97 (ADGRE5) is an adhesion G protein-coupled receptor (aGPCR) which plays crucial roles in immune system and cancer. However, the mechanism of CD97 activation and the determinant of G₁₃ coupling selectivity remain unknown. Here, we present the cryo-electron microscopy structures of human CD97 in complex with G₁₃, G_q, and G_s. Our structures reveal the stalk peptide recognition mode of CD97, adding missing information of the current tethered-peptide activation model of aGPCRs. For instance, a revised "FXφφφ" motif and a framework of conserved aromatic residues in the ligand-binding pocket. Importantly, structural comparisons of G₁₃, G_q, and G_s engagements of CD97 reveal key determinants of G₁₃ coupling selectivity, where a deep insertion of the α helix 5 and a closer contact with the transmembrane helix 6, 5, and 3 dictate coupling preferences. Taken together, our structural study of CD97 provides a framework for understanding CD97 signaling and the G₁₃ coupling selectivity.

Keywords: CD97; G(13) coupling; G-protein coupling selectivity; aGPCR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
GTP-Binding Proteins*
Humans
Peptides
Receptors, G-Protein-Coupled* / metabolism
Signal Transduction

Substances

GTP-Binding Proteins
Peptides
Receptors, G-Protein-Coupled
ADGRE5 protein, human