title: Structural basis for amyloidogenic peptide recognition by sorLA.
abstract: SorLA is a neuronal sorting receptor considered to be a major risk factor for Alzheimer's disease. We have recently reported that it directs lysosomal targeting of nascent neurotoxic amyloid-β (Aβ) peptides by directly binding Aβ. Here, we determined the crystal structure of the human sorLA domain responsible for Aβ capture, Vps10p, in an unbound state and in complex with two ligands. Vps10p assumes a ten-bladed β-propeller fold with a large tunnel at the center. An internal ligand derived from the sorLA propeptide bound inside the tunnel to extend the β-sheet of one of the propeller blades. The structure of the sorLA Vps10p-Aβ complex revealed that the same site is used. Peptides are recognized by sorLA Vps10p in redundant modes without strict dependence on a particular amino acid sequence, thus suggesting a broad specificity toward peptides with a propensity for β-sheet formation.
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Yu
authors: Y
authors: Kitago
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Masamichi
authors: M
authors: Nagae
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Zenzaburo
authors: Z
authors: Nakata
authors: 1] Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan. [2] Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors: Maho
authors: M
authors: Yagi-Utsumi
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Shizuka
authors: S
authors: Takagi-Niidome
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Emiko
authors: E
authors: Mihara
authors: Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
authors: Terukazu
authors: T
authors: Nogi
authors: 1] Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, Japan. [2] Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors: Koichi
authors: K
authors: Kato
authors: Institute for Protein Research, Osaka University, Suita, Japan.
authors: Junichi
authors: J
authors: Takagi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human
references: J Biol Chem. 2001 Jun 22;276(25):22788-96
references: 11294867
references: J Neurosci. 2008 Nov 26;28(48):12877-86
references: 19036982
references: Nat Rev Neurosci. 2008 Dec;9(12):899-909
references: 19002190
references: Trends Biochem Sci. 2005 Jun;30(6):309-17
references: 15950875
references: FEBS Lett. 2013 Jun 5;587(11):1605-9
references: 23603391
references: Arch Neurol. 2004 Aug;61(8):1200-5
references: 15313836
references: Bioinformatics. 2013 Apr 1;29(7):845-54
references: 23407358
references: Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17772-7
references: 19008353
references: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references: 19461840
references: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
references: 20057044
references: J Comput Chem. 2004 Oct;25(13):1656-76
references: 15264259
references: Neuron. 2004 Aug 5;43(3):333-44
references: 15294142
references: Nat Struct Mol Biol. 2009 Jan;16(1):96-8
references: 19122660
references: Nat Protoc. 2011 Mar;6(3):365-87
references: 21372817
references: Nat Genet. 2007 Feb;39(2):168-77
references: 17220890
references: Sci Transl Med. 2014 Feb 12;6(223):223ra20
references: 24523320
references: Arterioscler Thromb Vasc Biol. 2007 May;27(5):1050-6
references: 17332490
references: Cell. 1994 May 20;77(4):579-86
references: 8187177
references: Acc Chem Res. 2013 Jul 16;46(7):1487-96
references: 23294335
references: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6
references: 16174740
references: J Biol Chem. 1996 Dec 6;271(49):31379-83
references: 8940146
references: Int J Dev Biol. 1996 Feb;40(1):339-44
references: 8735946
references: Mol Psychiatry. 2012 Sep;17(9):875-9
references: 22472873
references: J Cell Sci. 2006 Feb 1;119(Pt 3):542-9
references: 16443751
references: J Biol Chem. 1996 Oct 4;271(40):24761-8
references: 8798746
references: Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1501-6
references: 11557679
references: Nat Chem Biol. 2009 Jan;5(1):15-22
references: 19088715
references: Nucleic Acids Res. 1990 Sep 11;18(17):5322
references: 1698283
references: Int J Alzheimers Dis. 2010 Dec 28;2011:925073
references: 21318130
references: Methods Enzymol. 1997;276:307-26
references: 27754618
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references: 20124702
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: Hum Mutat. 2008 May;29(5):769-70
references: 18407551
references: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
references: 21460454
references: J Proteomics. 2010 Aug 5;73(9):1777-85
references: 20566373
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Protein Eng Des Sel. 2007 Oct;20(10):521-3
references: 17720750
references: Protein Expr Purif. 2014 Mar;95:240-7
references: 24480187
references: Methods Enzymol. 2000;327:19-35
references: 11044971
references: Development. 1999 Sep;126(18):4077-86
references: 10457016
references: Mol Cell Biol. 1989 Feb;9(2):377-83
references: 2710109
references: Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11361-6
references: 23798407
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Jan 1;67(Pt 1):129-32
references: 21206043
references: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
references: 20057045
references: J Chem Theory Comput. 2008 Mar;4(3):435-47
references: 26620784