8SYN

Human VPS35L/VPS29/VPS26C Complex

Summary for 8SYN

• Entry DOI: 10.2210/pdb8syn/pdb
• EMDB information: 40884 40885 40886
• Descriptor: VPS35 endosomal protein-sorting factor-like, Vacuolar protein sorting-associated protein 29, Vacuolar protein sorting-associated protein 26C (3 entities in total)
• Functional Keywords: commd, retriever, commander, ccc, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 165788.12

Authors

Chen, Z.,Chen, B.,Burstein, E.,Han, Y. (deposition date: 2023-05-25, release date: 2023-11-01, Last modification date: 2024-07-03)

Primary citation

Boesch, D.J.,Singla, A.,Han, Y.,Kramer, D.A.,Liu, Q.,Suzuki, K.,Juneja, P.,Zhao, X.,Long, X.,Medlyn, M.J.,Billadeau, D.D.,Chen, Z.,Chen, B.,Burstein, E.
Structural organization of the retriever-CCC endosomal recycling complex.
Nat.Struct.Mol.Biol., 31:910-924, 2024

PubMed Abstract: The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of vacuolar protein-sorting-associated protein (VPS)35L, VPS26C and VPS29, together with the CCC complex comprising coiled-coil domain-containing (CCDC)22, CCDC93 and copper metabolism domain-containing (COMMD) proteins, plays a crucial role in this process. The precise mechanisms underlying retriever assembly and its interaction with CCC have remained elusive. Here, we present a high-resolution structure of retriever in humans determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog retromer. By combining AlphaFold predictions and biochemical, cellular and proteomic analyses, we further elucidate the structural organization of the entire retriever-CCC complex across evolution and uncover how cancer-associated mutations in humans disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with retriever-CCC-mediated endosomal recycling.

PubMed: 38062209
DOI: 10.1038/s41594-023-01184-4

Experimental method

ELECTRON MICROSCOPY (2.94 Å)