Amazing stuff!
"... Found throughout the human body, the 16-strong protein group called the Commander complex is involved with myriad biological functions including mounting our immune response, maintaining homeostasis in cells, and working as sort of a delivery and routing system. ...
One of the findings from the studies showed that all of the proteins in the Commander complex act together to carry out its activities. ..."
One of the findings from the studies showed that all of the proteins in the Commander complex act together to carry out its activities. ..."
"... This protein transport system is implicated in many diseases including heart disease, Alzheimer’s disease and infections. ...
This work provides a molecular explanation for the coupling of the CCC and Retriever assemblies into the holo-Commander complex. Although our model will require full structural confirmation, we show that mutations designed based on AlphaFold2 modeling specifically block CCC and Retriever interaction. Our data thus support the idea that while the CCC and Retriever assemblies are distinct structures, the function of these proteins likely depends on their incorporation into the Commander holo-assembly. ..."
This work provides a molecular explanation for the coupling of the CCC and Retriever assemblies into the holo-Commander complex. Although our model will require full structural confirmation, we show that mutations designed based on AlphaFold2 modeling specifically block CCC and Retriever interaction. Our data thus support the idea that while the CCC and Retriever assemblies are distinct structures, the function of these proteins likely depends on their incorporation into the Commander holo-assembly. ..."
From the highlights and abstract:
"Highlights
• 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
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."
AI helps map the postal workers in cells (University of Queensland news release)
Graphical abstract
A 3D model of the Commander complex.
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