Structural Organization of the Retriever-CCC Endosomal Recycling Complex.

Autor:	Boesch DJ; Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, 2437 Pammel Drive, Ames, IA 50011, USA., Singla A; Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA., Han Y; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA., Kramer DA; Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, 2437 Pammel Drive, Ames, IA 50011, USA., Liu Q; Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA., Suzuki K; Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA., Juneja P; Cryo-EM facility, Office of Biotechnology, Iowa State University, 2437 Pammel Drive, Ames, IA 50011, USA., Zhao X; Research IT, College of Liberal Arts and Sciences, Iowa State University, 2415 Osborn Dr, Ames, IA 50011, USA., Long X; Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA., Medlyn MJ; Division of Oncology Research, College of Medicine, Mayo Clinic, Rochester MN, 55905, USA., Billadeau DD; Division of Oncology Research, College of Medicine, Mayo Clinic, Rochester MN, 55905, USA., Chen Z; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA., Chen B; Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, 2437 Pammel Drive, Ames, IA 50011, USA., Burstein E; Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Jun 16. Date of Electronic Publication: 2023 Jun 16.
DOI:	10.21203/rs.3.rs-3026818/v1
Abstrakt:	The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and 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 the first high-resolution structure of Retriever 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 and uncover how cancer-associated mutations 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.
Databáze:	MEDLINE
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