The reticulons and receptor expression-enhancing proteins (REEPs) in the endoplasmic reticulum (ER) are necessary and sufficient for generating ER tubules. However, the mechanism of curvature generation remains elusive. Here, we systematically analyze components of the REEP family based on AI-predicted structures. In yeast REEP Yop1p, TM1/2 and TM3/4 form hairpins and TM2-4 exist as a bundle. Site-directed cross-linking reveals that TM2 and TM4 individually mediate homotypic dimerization, allowing further assembly into a curved shape. Truncated Yop1p lacking TM1 (equivalent to REEP1) retains the curvature-generating capability, undermining the role of the intrinsic wedge. Unexpectedly, both REEP1 and REEP5 fail to replace Yop1p in the maintenance of ER morphology, mostly due to a subtle difference in oligomerization tendency, which involves not only the TM domains, but also the TM-connecting cytosolic loop and previously neglected C-terminal helix. Several hereditary spastic paraplegia-causing mutations in REEP1 appear at the oligomeric interfaces identified here, suggesting compromised self-association of REEP as a pathogenic mechanism. These results indicate that membrane curvature stabilization by integral membrane proteins is dominantly achieved by curved, oligomeric scaffolding.

• PMID: 37147312
• DOI full text
• PMC full text
• PubMed
• PubTator

Reference Type

Journal Article | Research Support, Non-U.S. Gov't

Authors

Xiang Y, Lyu R, Hu J

Primary Lit For

Additional Lit For

Review For