Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome
The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-...
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Published in | Cell Vol. 186; no. 10; pp. 2219 - 2237.e29 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
11.05.2023
Cell Press |
Subjects | |
Online Access | Get full text |
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Summary: | The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed of VPS35L, VPS26C, and VPS29; and the CCC complex which contains twelve subunits: COMMD1-COMMD10 and the coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy, and in silico predictions, we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilized by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a 16th subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.
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•CryoEM, crystal and modeled structure of the trimeric Retriever complex•Crystal and CryoEM structures of the CCC complex•Model and functional validation of the holo-Commander complex•Disease-causing mutations in Commander perturb stability and subunit interactions
Complete structural model and functional validation of the sixteen-subunit human Commander complex reveals mechanisms of assembly and how mutations causing Ritscher-Schinzel syndrome perturb stability and subunit interactions of this evolutionarily conserved trafficking machinery. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Senior authors These authors contributed equally Lead contact |
ISSN: | 0092-8674 1097-4172 1097-4172 |
DOI: | 10.1016/j.cell.2023.04.003 |