The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain

Hang Shi^1, 3, 4, Raul Rojas^2, 4, Juan S Bonifacino² & James H Hurley¹

¹  Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.

²  Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland 20892, USA.

³  Present address: The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

⁴  These authors contributed equally to this work.

The mammalian retromer complex consists of SNX1, SNX2, Vps26, Vps29 and Vps35, and retrieves lysosomal enzyme receptors from endosomes to the trans-Golgi network. The structure of human Vps26A at 2.1-Å resolution reveals two curved -sandwich domains connected by a polar core and a flexible linker. Vps26 has an unpredicted structural relationship to arrestins. The Vps35-binding site on Vps26 maps to a mobile loop spanning residues 235–246, near the tip of the C-terminal domain. The loop is phylogenetically conserved and provides a mechanism for Vps26 integration into the complex that leaves the rest of the structure free for engagements with membranes and for conformational changes. Hydrophobic residues and a glycine in this loop are required for integration into the retromer complex and endosomal localization of human Vps26, and for the function of yeast Vps26 in carboxypeptidase Y sorting.

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