Structural basis of the zinc-induced cytoplasmic aggregation of the RNA-binding protein SFPQ.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
06 04 2020
06 04 2020
Historique:
accepted:
28
01
2020
revised:
23
01
2020
received:
14
11
2019
pubmed:
9
2
2020
medline:
23
5
2020
entrez:
9
2
2020
Statut:
ppublish
Résumé
SFPQ is a ubiquitous nuclear RNA-binding protein implicated in many aspects of RNA biogenesis. Importantly, nuclear depletion and cytoplasmic accumulation of SFPQ has been linked to neuropathological conditions such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Here, we describe a molecular mechanism by which SFPQ is mislocalized to the cytoplasm. We report an unexpected discovery of the infinite polymerization of SFPQ that is induced by zinc binding to the protein. The crystal structure of human SFPQ in complex with zinc at 1.94 Å resolution reveals intermolecular interactions between SFPQ molecules that are mediated by zinc. As anticipated from the crystal structure, the application of zinc to primary cortical neurons induced the cytoplasmic accumulation and aggregation of SFPQ. Mutagenesis of the three zinc-coordinating histidine residues resulted in a significant reduction in the zinc-binding affinity of SFPQ in solution and the zinc-induced cytoplasmic aggregation of SFPQ in cultured neurons. Taken together, we propose that dysregulation of zinc availability and/or localization in neuronal cells may represent a mechanism for the imbalance in the nucleocytoplasmic distribution of SFPQ, which is an emerging hallmark of neurodegenerative diseases including AD and ALS.
Identifiants
pubmed: 32034402
pii: 5730376
doi: 10.1093/nar/gkaa076
pmc: PMC7102971
doi:
Substances chimiques
PTB-Associated Splicing Factor
0
RNA-Binding Proteins
0
RNA
63231-63-0
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3356-3365Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Acta Crystallogr D Biol Crystallogr. 2011 Nov;67(Pt 11):981-7
pubmed: 22101825
Front Aging Neurosci. 2014 Apr 17;6:77
pubmed: 24860495
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
pubmed: 20057044
Front Aging Neurosci. 2013 Jul 19;5:33
pubmed: 23882214
Nucleic Acids Res. 2016 May 19;44(9):3989-4004
pubmed: 27084935
PLoS One. 2012;7(4):e35678
pubmed: 22558197
J Synchrotron Radiat. 2018 May 1;25(Pt 3):885-891
pubmed: 29714201
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Cell Rep. 2015 Feb 10;10(5):783-795
pubmed: 25660027
Front Cell Neurosci. 2017 May 03;11:124
pubmed: 28515681
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Mol Cell. 1998 May;1(6):849-61
pubmed: 9660968
Nat Commun. 2017 Jun 29;8(1):45
pubmed: 28663553
Dev Dyn. 2007 May;236(5):1347-57
pubmed: 17393485
Wiley Interdiscip Rev RNA. 2015 Jul-Aug;6(4):351-67
pubmed: 25832716
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
pubmed: 21460441
Nat Commun. 2018 May 22;9(1):2010
pubmed: 29789581
Front Aging Neurosci. 2014 Feb 11;6:15
pubmed: 24575040
Exp Gerontol. 2008 May;43(5):488-92
pubmed: 18068923
Sci Rep. 2017 Jul 28;7(1):6812
pubmed: 28754988
RNA. 2015 Dec;21(12):2023-9
pubmed: 26428695
Nat Rev Neurosci. 2005 Jun;6(6):449-62
pubmed: 15891778
Neurology. 2006 Jul 11;67(1):69-75
pubmed: 16832080
J Biol Chem. 2018 Apr 27;293(17):6593-6602
pubmed: 29530979
Acta Crystallogr F Struct Biol Commun. 2019 Jun 1;75(Pt 6):439-449
pubmed: 31204691
ACS Chem Biol. 2015 Jun 19;10(6):1511-20
pubmed: 25786639
Nat Neurosci. 2016 May;19(5):690-696
pubmed: 27019013
Neuron. 2017 Apr 19;94(2):322-336.e5
pubmed: 28392072
Nucleic Acids Res. 2015 Apr 20;43(7):3826-40
pubmed: 25765647
Brain. 2019 May 1;142(5):1176-1194
pubmed: 30938443
Acta Crystallogr D Biol Crystallogr. 2013 Jul;69(Pt 7):1204-14
pubmed: 23793146
Cell Rep. 2018 May 1;23(5):1326-1341
pubmed: 29719248
Int J Alzheimers Dis. 2010 Dec 20;2011:971021
pubmed: 21197404
Neuron. 2019 Apr 17;102(2):294-320
pubmed: 30998900
Cell Rep. 2017 Jan 31;18(5):1118-1131
pubmed: 28147269
Neurobiol Dis. 2009 May;34(2):221-9
pubmed: 19344646
Front Mol Neurosci. 2017 Apr 04;10:89
pubmed: 28420962
Genes Dev. 2017 Aug 1;31(15):1509-1528
pubmed: 28912172
Molecules. 2017 Aug 29;22(9):
pubmed: 28850080
Free Radic Biol Med. 2010 May 1;48(9):1152-61
pubmed: 20138212
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
J Alzheimers Dis. 2018;61(4):1311-1321
pubmed: 29376859