The retromer complex is required for the sorting of acid hydrolases to lysosomes, transcytosis of the polymeric Ig receptor, Wnt gradient formation, iron transporter recycling, and processing of the amyloid precursor protein. Human retromer consists of two smaller complexes, the cargo recognition Vps26:Vps29:Vps35 heterotrimer, and a membrane-targeting heterodimer or homodimer of SNX1 andor SNX2. The retromer cargo recognition complex consists of the 38-kDa Vps26, 20-kDa Vps29, and 92-kDa Vps35 subunits. In 2006 this laboratory used x-ray crystallography to show that Vps26 is a structural cousin of the arrestins, a family of trafficking proteins that directly bind to cell surface receptors and direct their internalization. Juan Bonifacinos laboratory, working in collaboration with our group, showed that Vps26 binds to Vps35 through a conserved loop in the C-terminal lobe, and found that this loop is required for the correct localization of Vps26 in vivo. Vps29 was shown by two other labs to have a metallophosphoesterase fold that can bind two metal ions. Compared to functional metallophosphoesterases, a key His that serves as a catalytic base in the metallophosphoesterase active site is replaced by Phe 63. Thus Vps29 is completely inactive with respect to generic phosphatase substrates. However, metal-dependent activity in vitro against a phosphorylated peptide from a major retromer cargo, the cation-independent mannose 6-phosphate receptor (CI-MPR), has been reported. Despite its centrality to multiple trafficking pathways, the precise function of retromer has been enigmatic. Various proposals have emphasized potential roles as a coat, adaptor, or cargo protein phosphatase. Current studies are taking a structural approach to resolving this question.
| Bonifacino, Juan S; Hurley, James H (2008) Retromer. Curr Opin Cell Biol 20:427-36 |
| Hierro, Aitor; Rojas, Adriana L; Rojas, Raul et al. (2007) Functional architecture of the retromer cargo-recognition complex. Nature 449:1063-7 |
| Shi, Hang; Rojas, Raul; Bonifacino, Juan S et al. (2006) The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol 13:540-8 |
