title: A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer.
abstract: The sorting nexin 27 (SNX27)-retromer complex is a major regulator of endosome-to-plasma membrane recycling of transmembrane cargos that contain a PSD95, Dlg1, zo-1 (PDZ)-binding motif. Here we describe the core interaction in SNX27-retromer assembly and its functional relevance for cargo sorting. Crystal structures and NMR experiments reveal that an exposed β-hairpin in the SNX27 PDZ domain engages a groove in the arrestin-like structure of the vacuolar protein sorting 26A (VPS26A) retromer subunit. The structure establishes how the SNX27 PDZ domain simultaneously binds PDZ-binding motifs and retromer-associated VPS26. Importantly, VPS26A binding increases the affinity of the SNX27 PDZ domain for PDZ- binding motifs by an order of magnitude, revealing cooperativity in cargo selection. With disruption of SNX27 and retromer function linked to synaptic dysfunction and neurodegenerative disease, our work provides the first step, to our knowledge, in the molecular description of this important sorting complex, and more broadly describes a unique interaction between a PDZ domain and an arrestin-like fold.
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Matthew
authors.initials: M
authors.lastname: Gallon
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clairfeuille
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom;
authors.forename: Florian
authors.initials: F
authors.lastname: Steinberg
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mas
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ghai
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sessions
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and.
authors.forename: Rohan D
authors.initials: RD
authors.lastname: Teasdale
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; and b.collins@imb.uq.edu.au pete.cullen@bristol.ac.uk.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.affiliation: The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom; b.collins@imb.uq.edu.au pete.cullen@bristol.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000235:genetics; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018360:Crystallography, X-Ray; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054731:PDZ Domains / Q000235:genetics*; D017510:Protein Folding; D021382:Protein Sorting Signals / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017386:Sequence Homology, Amino Acid; D058305:Sorting Nexins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D019393:Arrestin; D009419:Nerve Tissue Proteins; D021382:Protein Sorting Signals; D034741:RNA, Small Interfering; C522885:SNX27 protein, human; C500393:Snx27 protein, mouse; C477690:Snx27 protein, rat; D058305:Sorting Nexins; C498296:VPS26A protein, human; D033921:Vesicular Transport Proteins; C089989:Vps26 protein, mouse
keywords: Alzheimer's disease; Down syndrome; Parkinson disease; endosomal recycling