title: Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase.
abstract: Mucopolysaccharidosis type I (MPS I), caused by mutations in the gene encoding α-L-iduronidase (IDUA), is one of approximately 70 genetic disorders collectively known as the lysosomal storage diseases. To gain insight into the basis for MPS I, we crystallized human IDUA produced in an Arabidopsis thaliana cgl mutant. IDUA consists of a TIM barrel domain containing the catalytic site, a β-sandwich domain and a fibronectin-like domain. Structures of IDUA bound to iduronate analogs illustrate the Michaelis complex and reveal a (2,5)B conformation in the glycosyl-enzyme intermediate, which suggest a retaining double displacement reaction involving the nucleophilic Glu299 and the general acid/base Glu182. Unexpectedly, the N-glycan attached to Asn372 interacts with iduronate analogs in the active site and is required for enzymatic activity. Finally, these IDUA structures and biochemical analysis of the disease-relevant P533R mutation have enabled us to correlate the effects of mutations in IDUA to clinical phenotypes.
authors.affiliation: 1] Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. [2] These authors contributed equally to this work.
authors.forename: Haiying
authors.initials: H
authors.lastname: Bie
authors.forename: Jiang
authors.initials: J
authors.lastname: Yin
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.forename: Allison R
authors.initials: AR
authors.lastname: Kermode
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Goddard-Borger
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
authors.forename: Michael N G
authors.initials: MN
authors.lastname: James
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D007068:Iduronidase / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008059:Mucopolysaccharidosis I / Q000201:enzymology* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D007068:Iduronidase
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):355-67
references.pmid: 21460454
references.citation: BMC Struct Biol. 2011 Jan 26;11:6
references.pmid: 21269479
references.citation: Am J Med Genet. 1985 Mar;20(3):471-81
references.pmid: 3922223
references.citation: Chem Biol. 1999 Jul;6(7):483-92
references.pmid: 10381409
references.citation: Nat Protoc. 2008;3(7):1171-9
references.pmid: 18600222
references.citation: Assay Drug Dev Technol. 2011 Jun;9(3):213-35
references.pmid: 21612550
references.citation: Plant Biotechnol J. 2013 Dec;11(9):1034-43
references.pmid: 23898885
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references.pmid: 20124692
references.citation: Acc Chem Res. 2012 Feb 21;45(2):308-16
references.pmid: 21923088
references.citation: Expert Rev Mol Med. 2008 Jan 18;10:e1
references.pmid: 18201392
references.citation: Mol Genet Metab. 2003 Jan;78(1):37-43
references.pmid: 12559846
references.citation: Mol Genet Metab. 2012 Jul;106(3):323-9
references.pmid: 22592100
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14628-33
references.pmid: 23959878
references.citation: Genet Med. 2003 Jul-Aug;5(4):286-94
references.pmid: 12865757
references.citation: J Mol Biol. 1999 Jan 29;285(4):1735-47
references.pmid: 9917408
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):439-50
references.pmid: 16552146
references.citation: Hum Mutat. 2004 Sep;24(3):199-207
references.pmid: 15300847
references.citation: Plant Biotechnol J. 2006 Mar;4(2):169-81
references.pmid: 17177794
references.citation: Clin Sci (Lond). 1982 Feb;62(2):193-201
references.pmid: 6895615
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references.pmid: 21460441
references.citation: Ann Hum Genet. 1999 Jan;63(Pt 1):9-16
references.pmid: 10738517
references.citation: FEBS J. 2007 Oct;274(19):4944-50
references.pmid: 17894779
references.citation: Angew Chem Int Ed Engl. 1999 Mar 15;38(6):750-770
references.pmid: 29711789
references.citation: J Inherit Metab Dis. 2005;28(6):1019-26
references.pmid: 16435195
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: Biochim Biophys Acta. 1998 Sep 30;1407(3):249-56
references.pmid: 9748610
references.citation: J Mol Biol. 2004 Jan 2;335(1):155-65
references.pmid: 14659747
references.citation: J Biol Chem. 1997 Sep 5;272(36):22758-65
references.pmid: 9278435
references.citation: Biochemistry. 1999 Apr 27;38(17):5346-54
references.pmid: 10220321
references.citation: Biochem J. 1998 Oct 15;335 ( Pt 2):449-55
references.pmid: 9761746
references.citation: Mol Plant Microbe Interact. 2007 Jul;20(7):740-50
references.pmid: 17601162
references.citation: Eur J Biochem. 1996 Mar 1;236(2):706-13
references.pmid: 8612648
references.citation: Nature. 2001 Aug 23;412(6849):835-8
references.pmid: 11518970
references.citation: Nat Commun. 2012;3:1062
references.pmid: 22990858
references.citation: Mol Genet Metab. 2005 May;85(1):28-37
references.pmid: 15862278
references.citation: Eur J Biochem. 1985 Oct 1;152(1):29-34
references.pmid: 4043083
references.citation: Plant Mol Biol. 2012 May;79(1-2):157-69
references.pmid: 22442036
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Methods Enzymol. 2003;374:300-21
references.pmid: 14696379
references.citation: Biochemistry. 2003 Jul 8;42(26):8054-65
references.pmid: 12834357
references.citation: Acta Crystallogr D Biol Crystallogr. 2000 Apr;56(Pt 4):524-8
references.pmid: 10739940
references.citation: Hum Mutat. 1992;1(4):333-9
references.pmid: 1301941
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: Chembiochem. 2008 Nov 3;9(16):2650-62
references.pmid: 18972510