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PDBsum entry 2r17

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Protein transport PDB id
2r17
Jmol
Contents
Protein chains
183 a.a.
298 a.a.
276 a.a.
Ligands
GOL ×2
Waters ×49

References listed in PDB file
Key reference
Title Functional architecture of the retromer cargo-Recognition complex.
Authors A.Hierro, A.L.Rojas, R.Rojas, N.Murthy, G.Effantin, A.V.Kajava, A.C.Steven, J.S.Bonifacino, J.H.Hurley.
Ref. Nature, 2007, 449, 1063-1067. [DOI no: 10.1038/nature06216]
PubMed id 17891154
Abstract
The retromer complex is required for the sorting of acid hydrolases to lysosomes, transcytosis of the polymeric immunoglobulin 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 and/or SNX2 (ref. 13). Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxy-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. Electron microscopy shows that the intact VPS26-VPS29-VPS35 complex is a stick-shaped, flexible structure, approximately 21 nm long. A hybrid structural model derived from crystal structures, electron microscopy, interaction studies and bioinformatics shows that the alpha-solenoid fold extends the full length of VPS35, and that VPS26 is bound at the opposite end from VPS29. This extended structure presents multiple binding sites for the SNX complex and receptor cargo, and appears capable of flexing to conform to curved vesicular membranes.
Figure 1.
Figure 1: Structure of the VPS29–VPS35 subcomplex. a, VPS29 is green and VPS35 red. b, The surface of VPS35 is shown, with the residues blocking the metallophosphoesterase site of VPS29 in grey, and other residues that contact VPS29 in purple. c, The surface of VPS29 is shown, with residues surrounding the metallophosphoesterase site in light blue, and other VPS35-contacting residues in purple. d, Hydrophobic grooves on the outer surface of VPS35 are formed between even-numbered helices. The probability of the surface to participate in ligand binding was coloured from lowest to highest in a blue to red gradient using the hotpatch server (http://hotpatch.mbi.ucla.edu/). Structural figures were generated with pymol (http://www.pymol.org/).
Figure 4.
Figure 4: Integration of cargo and targeting signals by the cargo-recognition complex. a, The VPS26–VPS29–VPS35 complex is predicted to align roughly parallel to the membrane (green line at bottom), such that its multiple SNX^4, ^15 and cargo-binding sites^25 cooperatively interact. The arrows mark the central region about which VPS35 is proposed to flex so as to interact with cargo embedded in curved membranes. Binding sites that have been mapped to individual residues within crystallized components are coloured dark blue. Binding sites that have been mapped to regions of VPS35 or to as yet non-crystallized portions of VPS35 are marked by red bars aligned with the region of interest. Binding sites for yeast cargo proteins are not necessarily conserved in human VPS35; however, the overall architecture of the yeast and other orthologous complexes is proposed to be very similar to the human complex. b, Schematic rendering of a speculative model for the retromer coat on a tubular vesicle, coloured as above, with the SNX dimer in purple.
The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 449, 1063-1067) copyright 2007.
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