title: Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants.
abstract: The copper-zinc superoxide dismutase-1 (SOD1) is a highly structured protein and, a priori, one of the least likely proteins to be involved in a misfolding disease. However, more than 140, mostly missense, mutations in the SOD1 gene cause aggregation of the affected protein in familial forms of amyotrophic lateral sclerosis (ALS). The remarkable diversity of the effects of these mutations on SOD1 properties has suggested that they promote aggregation by a variety of mechanisms. Experimental assessment of surface hydrophobicity using a sensitive fluorescent-based assay, revealed that diverse ALS-causing mutations provoke SOD1 aggregation by increasing their propensity to expose hydrophobic surfaces. These findings could not be anticipated from analysis of the amino acid sequence. Our results uncover the biochemical nature of the misfolded aggregation-prone intermediate and reconcile the seemingly diverse effects of ALS-causing mutations into a unifying mechanism. Furthermore, the method we describe here will be useful for investigating and interfering with aggregation of various proteins and thereby provide insight into the molecular mechanisms underlying many neurodegenerative diseases.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Münch
authors.forename: Anne
authors.initials: A
authors.lastname: Bertolotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D005453:Fluorescence; D005456:Fluorescent Dyes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009154:Mutation; D011487:Protein Conformation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: D005456:Fluorescent Dyes; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: J Mol Biol. 2009 Jan 9;385(1):278-98
references.pmid: 18951903
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15893-8
references.pmid: 15522970
references.citation: Annu Rev Neurosci. 2004;27:723-49
references.pmid: 15217349
references.citation: Science. 1993 Aug 20;261(5124):1047-51
references.pmid: 8351519
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9754-9
references.pmid: 15987780
references.citation: Science. 1998 Sep 18;281(5384):1851-4
references.pmid: 9743498
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7774-9
references.pmid: 19416874
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10516-21
references.pmid: 16020530
references.citation: J Biol Chem. 2005 Aug 19;280(33):29771-9
references.pmid: 15958382
references.citation: Nat Genet. 1996 May;13(1):43-7
references.pmid: 8673102
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7021-6
references.pmid: 12773627
references.citation: J Biol Chem. 2004 Nov 12;279(46):47998-8003
references.pmid: 15326189
references.citation: J Biol Chem. 2008 Aug 29;283(35):24167-76
references.pmid: 18552350
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14157-62
references.pmid: 17715066
references.citation: J Biol Chem. 2007 Jan 5;282(1):345-52
references.pmid: 17092942
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9648-53
references.pmid: 15210964
references.citation: J Biol Chem. 2009 Oct 2;284(40):27746-58
references.pmid: 19651777
references.citation: J Neuropathol Exp Neurol. 1996 Apr;55(4):481-90
references.pmid: 8786408
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1392-7
references.pmid: 19171884
references.citation: J Biol Chem. 2009 Dec 4;284(49):34382-9
references.pmid: 19805550
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11263-7
references.pmid: 17592131
references.citation: J Mol Biol. 2007 Nov 23;374(2):454-64
references.pmid: 17936783
references.citation: Brain. 2004 Jan;127(Pt 1):73-88
references.pmid: 14534160
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3590-4
references.pmid: 10097081
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5976-81
references.pmid: 15056757
references.citation: J Mol Biol. 1988 Jun 5;201(3):621-3
references.pmid: 3418713
references.citation: PLoS Biol. 2008 Jul 29;6(7):e170
references.pmid: 18666828
references.citation: HFSP J. 2008 Dec;2(6):354-64
references.pmid: 19436494
references.citation: Nat Struct Biol. 2003 Jun;10(6):461-7
references.pmid: 12754496
references.citation: Annu Rev Biochem. 2005;74:563-93
references.pmid: 15952898
references.citation: Neuropathology. 2001 Mar;21(1):67-81
references.pmid: 11304045
references.citation: J Biol Chem. 2002 May 3;277(18):15923-31
references.pmid: 11854284
references.citation: Pharm Res. 2008 Jul;25(7):1487-99
references.pmid: 18172579
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):4022-7
references.pmid: 18296640
references.citation: EMBO J. 2007 Feb 7;26(3):855-66
references.pmid: 17255946
references.citation: J Biol Chem. 2007 Jul 20;282(29):21230-6
references.pmid: 17513298
references.citation: J Mol Biol. 2003 Sep 19;332(3):601-15
references.pmid: 12963370
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16607-12
references.pmid: 12482932
references.citation: J Biol Chem. 2002 Dec 6;277(49):47551-6
references.pmid: 12356748
references.citation: Hum Mol Genet. 1999 Aug;8(8):1451-60
references.pmid: 10400992
references.citation: J Biol Chem. 2003 Feb 21;278(8):5984-92
references.pmid: 12458194
references.citation: J Neurol Sci. 2004 Oct 15;225(1-2):19-25
references.pmid: 15465081
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18663-8
references.pmid: 19022905
references.citation: J Biol Chem. 1995 Feb 17;270(7):3234-8
references.pmid: 7852409
references.citation: J Biol Chem. 2009 May 15;284(20):13940-13947
references.pmid: 19299510
references.citation: Neurobiol Dis. 2002 Jul;10(2):128-38
references.pmid: 12127151
references.citation: J Biol Chem. 2009 Jan 16;284(3):1917-29
references.pmid: 18986984
references.citation: Am J Pathol. 1997 Aug;151(2):611-20
references.pmid: 9273821
references.citation: Nature. 2003 Aug 14;424(6950):805-8
references.pmid: 12917692
references.citation: Proteins. 2005 Nov 15;61(3):617-32
references.pmid: 16152647
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15094-9
references.pmid: 15475574
references.citation: Cell Mol Life Sci. 2007 Oct;64(19-20):2525-41
references.pmid: 17565442
references.citation: Anal Biochem. 2004 Sep 1;332(1):153-9
references.pmid: 15301960