Structural Predictions of the SNX-RGS Proteins Suggest They Belong to a New Class of Lipid Transfer Proteins

Blessy Paul, Saroja Weeratunga, Vikas A. Tillu, Hanaa Hariri, W. Mike Henne, Brett M. Collins

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Recent advances in protein structure prediction using machine learning such as AlphaFold2 and RosettaFold presage a revolution in structural biology. Genome-wide predictions of protein structures are providing unprecedented insights into their architecture and intradomain interactions, and applications have already progressed towards assessing protein complex formation. Here we present detailed analyses of the sorting nexin proteins that contain regulator of G-protein signalling domains (SNX-RGS proteins), providing a key example of the ability of AlphaFold2 to reveal novel structures with previously unsuspected biological functions. These large proteins are conserved in most eukaryotes and are known to associate with lipid droplets (LDs) and sites of LD-membrane contacts, with key roles in regulating lipid metabolism. They possess five domains, including an N-terminal transmembrane domain that anchors them to the endoplasmic reticulum, an RGS domain, a lipid interacting phox homology (PX) domain and two additional domains named the PXA and PXC domains of unknown structure and function. Here we report the crystal structure of the RGS domain of sorting nexin 25 (SNX25) and show that the AlphaFold2 prediction closely matches the experimental structure. Analysing the full-length SNX-RGS proteins across multiple homologues and species we find that the distant PXA and PXC domains in fact fold into a single unique structure that notably features a large and conserved hydrophobic pocket. The nature of this pocket strongly suggests a role in lipid or fatty acid binding, and we propose that these molecules represent a new class of conserved lipid transfer proteins.

Original languageEnglish (US)
Article number826688
JournalFrontiers in Cell and Developmental Biology
Volume10
DOIs
StatePublished - Feb 3 2022

Keywords

  • AlphaFold2
  • lipid droplets (LDs)
  • lipid transfer protein (LTP)
  • phox homology (PX) domain
  • regulator of G-protein signaling (RGS)
  • sorting nexin (SNX)
  • X-ray crystallography

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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