VARP binds SNX27 to promote endosomal supercomplex formation on membranes.

ABSTRACT: Multiple essential membrane trafficking pathways converge at endosomes to maintain cellular homeostasis by sorting critical transmembrane cargo proteins to the plasma membrane or the trans-Golgi network (TGN). The Retromer heterotrimer (VPS26/VPS35/VPS29 subunits) binds multiple sorting nexin (SNX) proteins on endosomal membranes, but molecular mechanisms regarding formation and regulation of metazoan SNX/Retromer complexes have been elusive. Here, we combine biochemical and biophysical approaches with AlphaFold2 Multimer modeling to identify a direct interaction between the VARP N-terminus and SNX27 PDZ domain. VARP and SNX27 interact with high nanomolar affinity using the binding pocket established for PDZ binding motif (PDZbm) cargo. Specific point mutations in VARP abrogate the

SUBMITTER: Chandra M 

PROVIDER: S-EPMC11257539 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature