Structure of the human systemic RNAi defective transmembrane protein 1 (hSIDT1) reveals the conformational flexibility of its lipid binding domain.

In C. elegans , the inter-cellular transport of the small non-coding RNA that causes systemic RNA interference (RNAi) is mediated by the transmembrane protein SID1, encoded by the sid1 gene in the systemic RNA interference-defective ( sid ) loci. SID1 shares remarkable structural and sequence similarity with cholesterol uptake protein 1 (CHUP1), and they are classified together as members of the cholesterol uptake family (ChUP). Although systemic RNAi is not an evolutionarily conserved process, the sid gene products are found across the animal kingdom, suggesting a potential for the existence of other novel gene regulatory mechanisms mediated by small non-coding RNAs. Human homologs of sid gene products - hSIDT1 and hSIDT2 - are believed to mediate contact-dependent lipophilic small non-coding dsRNA transport. Here, we report the structure of recombinant full-length human SIDT1. We find that the extra-cytosolic domain (ECD) of hSIDT1 adopts a double jelly roll fold, and the transmembrane domain (TMD) exists as two modules - a flexible lipid binding domain (LBD) and a rigid TMD core. Our structural analyses provide insights into the potential role of the lipid binding domain in the function of hSIDT1 and other cholesterol uptake (ChUP) family members.