Unusual RNA binding of FUS RRM studied by molecular dynamics simulation and enhanced sampling method.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
04 05 2021
04 05 2021
Historique:
received:
29
09
2020
revised:
10
02
2021
accepted:
01
03
2021
pubmed:
12
3
2021
medline:
1
6
2021
entrez:
11
3
2021
Statut:
ppublish
Résumé
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobe degeneration (FTLD) are two inter-related intractable diseases of motor neuron degeneration. Fused in sarcoma (FUS) is found in cytoplasmic accumulation of ALS and FTLD patients, which readily link the protein with the diseases. The RNA recognition motif (RRM) of FUS has the canonical α-β folds along with an unusual lysine-rich loop (KK-loop) between α1 and β2. This KK-loop is highly conserved among FET family proteins. Another contrasting feature of FUS RRM is the absence of critical binding residues, which are otherwise highly conserved in canonical RRMs. These residues in FUS RRM are Thr286, Glu336, Thr338, and Ser367, which are substitutions of lysine, phenylalanine, phenylalanine, and lysine, respectively, in other RRMs. Considering the importance of FUS in RNA regulation and metabolism, and its implication in ALS and FTLD, it is important to elucidate the underlying molecular mechanism of RNA recognition. In this study, we have performed molecular dynamics simulation with enhanced sampling to understand the conformational dynamics of noncanonical FUS RRM and its binding with RNA. We studied two sets of mutations: one with alanine mutation of KK-loop and another with KK-loop mutations along with critical binding residues mutated back to their canonical form. We find that concerted movement of KK-loop and loop between β2 and β3 facilitates the folding of the partner RNA, indicating an induced-fit mechanism of RNA binding. Flexibility of the RRM is highly restricted upon mutating the lysine residues of the KK-loop, resulting in weaker binding with the RNA. Our results also suggest that absence of the canonical residues in FUS RRM along with the KK-loop is equally important in regulating its binding dynamics. This study provides a significant structural insight into the binding of FUS RRM with its cognate RNA, which may further help in designing potential drugs targeting noncanonical RNA recognition.
Identifiants
pubmed: 33705755
pii: S0006-3495(21)00205-8
doi: 10.1016/j.bpj.2021.03.001
pmc: PMC8204339
pii:
doi:
Substances chimiques
FUS protein, human
0
RNA-Binding Protein FUS
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1765-1776Informations de copyright
Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Références
Sci Rep. 2017 Apr 21;7(1):1043
pubmed: 28432364
Chem Rev. 2016 Jun 8;116(11):6391-423
pubmed: 26889708
Nat Chem Biol. 2009 Nov;5(11):789-96
pubmed: 19841628
Cell. 2009 Mar 20;136(6):1001-4
pubmed: 19303844
J Biomol Struct Dyn. 1996 Feb;13(4):615-25
pubmed: 8906882
J Mol Biol. 2016 Feb 22;428(4):720-725
pubmed: 26410586
Curr Opin Struct Biol. 2008 Jun;18(3):290-8
pubmed: 18515081
Sci Rep. 2017 Oct 3;7(1):12567
pubmed: 28974714
FEBS J. 2005 May;272(9):2118-31
pubmed: 15853797
PLoS Biol. 2011 Apr;9(4):e1000614
pubmed: 21541367
Nat Rev Neurol. 2014 Jun;10(6):337-48
pubmed: 24840975
Nucleic Acids Res. 2015 Sep 3;43(15):7535-43
pubmed: 26150427
Biophys J. 2018 Mar 27;114(6):1267-1273
pubmed: 29590584
Science. 2009 Feb 27;323(5918):1208-1211
pubmed: 19251628
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Int J Mol Sci. 2016 Feb 27;17(3):310
pubmed: 26927092
Nat Struct Biol. 2000 Oct;7(10):834-7
pubmed: 11017187
Neuron. 2013 Aug 7;79(3):416-38
pubmed: 23931993
Curr Alzheimer Res. 2011 May;8(3):273-94
pubmed: 21222600
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
pubmed: 10592235
Hum Mol Genet. 2013 Mar 15;22(6):1193-205
pubmed: 23257289
Sci Rep. 2015 Nov 27;5:17298
pubmed: 26612539
Biophys J. 2009 Dec 16;97(12):3139-49
pubmed: 20006951
Biochim Biophys Acta. 2013 Feb;1832(2):375-85
pubmed: 23200923
Int J Mol Sci. 2018 May 29;19(6):
pubmed: 29843482
J Biol Chem. 2001 Mar 2;276(9):6807-16
pubmed: 11098054
J Chem Theory Comput. 2018 Feb 13;14(2):991-997
pubmed: 29286646
Cell Mol Life Sci. 2016 Nov;73(21):4075-84
pubmed: 27229125
Mol Cell. 2019 Feb 7;73(3):490-504.e6
pubmed: 30581145
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4925-30
pubmed: 17360390
PLoS One. 2015 Oct 06;10(10):e0139731
pubmed: 26439842
J Chem Theory Comput. 2015 Mar 10;11(3):1308-14
pubmed: 26579776
Trends Genet. 2008 Aug;24(8):416-25
pubmed: 18597886
Nat Struct Biol. 1999 Dec;6(12):1081-3
pubmed: 10581539
J Mol Biol. 2009 Jan 9;385(1):312-29
pubmed: 18952103
J Mol Biol. 2010 Mar 12;396(5):1508-23
pubmed: 20083119
J Mol Biol. 2017 Feb 3;429(3):365-371
pubmed: 27964945
Sci China Life Sci. 2014 Apr;57(4):432-44
pubmed: 24658850
Sci Transl Med. 2017 Nov 8;9(415):
pubmed: 29118263
RNA Biol. 2016 Nov;13(11):1133-1143
pubmed: 27592836
PLoS Comput Biol. 2012;8(10):e1002709
pubmed: 23055912
Proteins. 2010 Jun;78(8):1950-8
pubmed: 20408171
Methods Mol Biol. 2016;1490:199-215
pubmed: 27665601
Sci Rep. 2019 Apr 16;9(1):6171
pubmed: 30992467