Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis.
Components of the Immune System
Molecular Neuroscience
Molecular Structure
Neuroscience
Protein Structure Aspects
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
27 Sep 2019
27 Sep 2019
Historique:
received:
08
09
2018
revised:
16
01
2019
accepted:
15
07
2019
pubmed:
2
8
2019
medline:
2
8
2019
entrez:
2
8
2019
Statut:
ppublish
Résumé
Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity toward sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, amyloid-β (Aβ), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aβ peptide that is thought to cause AD.
Identifiants
pubmed: 31369984
pii: S2589-0042(19)30248-2
doi: 10.1016/j.isci.2019.07.023
pmc: PMC6669322
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
110-118Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Neuron. 2013 May 22;78(4):631-43
pubmed: 23623698
J Biol Chem. 2003 Aug 15;278(33):31007-19
pubmed: 12773526
Nat Commun. 2017 Oct 2;8(1):764
pubmed: 28970495
Immunity. 2017 Sep 19;47(3):566-581.e9
pubmed: 28930663
Neurobiol Aging. 2015 Feb;36(2):571-82
pubmed: 25448602
J Neurosci. 2007 Aug 22;27(34):9201-19
pubmed: 17715356
J Neurosci. 2010 Mar 3;30(9):3482-8
pubmed: 20203208
J Biol Chem. 2006 Oct 27;281(43):32774-83
pubmed: 16895906
Science. 2009 Mar 27;323(5922):1722-5
pubmed: 19264983
Acta Crystallogr D Biol Crystallogr. 2004 Feb;60(Pt 2):401-3
pubmed: 14747738
Immunity. 2017 Sep 19;47(3):398-400
pubmed: 28930654
Nat Genet. 2011 May;43(5):436-41
pubmed: 21460841
Mol Neurodegener. 2017 Jun 29;12(1):50
pubmed: 28662669
Nat Genet. 2011 May;43(5):429-35
pubmed: 21460840
Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):E4170-9
pubmed: 27357658
Trends Biochem Sci. 2016 Jun;41(6):519-531
pubmed: 27085506
Biochem J. 2006 Jul 15;397(2):271-8
pubmed: 16623661
Hum Mol Genet. 2014 May 15;23(10):2729-36
pubmed: 24381305
J Mol Biol. 2008 Jan 11;375(2):437-47
pubmed: 18022638
Chem Sci. 2014 Jun 1;5(6):2398-2406
pubmed: 24921038
Nat Neurosci. 2018 Oct;21(10):1359-1369
pubmed: 30258234
Nat Genet. 2017 Sep;49(9):1373-1384
pubmed: 28714976
Mol Neurodegener. 2017 May 26;12(1):43
pubmed: 28549481
Neurol Genet. 2016 Jul 26;2(4):e90
pubmed: 27504496
Nat Neurosci. 2018 Jul;21(7):941-951
pubmed: 29950669
Blood. 2009 Apr 2;113(14):3333-6
pubmed: 19196661
Nat Rev Immunol. 2014 Jul;14(7):463-77
pubmed: 24962261
J Neurosci. 2013 Aug 14;33(33):13320-5
pubmed: 23946390
Nat Neurosci. 2013 Jul;16(7):848-50
pubmed: 23708142