title: Structural Mechanism for Cargo Recognition by the Retromer Complex.
abstract: Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment.
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Gershlick
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Vidaurrazaga
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain.
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Rojas
authors.affiliation: Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: bonifacinoj@helix.nih.gov.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain. Electronic address: ahierro@cicbiogune.es.
authors.forename: Aitor
authors.initials: A
authors.lastname: Hierro
mesh_terms: D000595:Amino Acid Sequence; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D053838:Scattering, Small Angle; D058305:Sorting Nexins / Q000737:chemistry* / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D000099236:Solute Carrier Family 11, Member 2; C513980:SNX3 protein, human; C498296:VPS26A protein, human; C419573:VPS35 protein, human
keywords: cargo recognition; endocytic recycling; endosomes; membrane recruitment; membrane tubules; protein coats; retrograde transport; retromer; sorting nexins; sorting signals