Crystal structure of a mammalian CMTM6 and its interaction model with PD-L1

Abstract

CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) is a master regulator of PD-L1. By binding PD-L1 at the plasma membrane and recycling endosomes, CMTM6 prevents the lysosomal degradation of PD-L1 and maintains its cell surface expression, thus stabilizing the inhibitory PD-1/PD-L1 axis. However, the mechanism of CMTM6/PD-L1 interaction is unknown. Here we report the first experimentally determined structure of CMTM6 from bovine. Combined with a low-resolution cryo-EM map, computational docking analysis and a protein binding assay an interaction model between CMTM6 and PD-L1 was proposed, providing a structural framework for the CMTM6 regulation on PD-L1.