Missense variant interaction scanning reveals a critical role of the FERM domain for tumor suppressor protein NF2 conformation and function.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
16
03
2023
revised:
24
05
2023
accepted:
24
05
2023
medline:
8
6
2023
pubmed:
7
6
2023
entrez:
6
6
2023
Statut:
epublish
Résumé
NF2 (moesin-ezrin-radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses. We identified two regions in NF2 with clustered mutations which affected conformation-dependent protein interactions. NF2 variants in the F2-F3 subdomain and the α3H helix region substantially modulated NF2 conformation and homomerization. Mutations in the F2-F3 subdomain altered proliferation in three cell lines and matched patterns of disease mutations in NF2 related-schwannomatosis. This study highlights the power of systematic mutational interaction perturbation analysis to identify missense variants impacting NF2 conformation and provides insight into NF2 tumor suppressor function.
Identifiants
pubmed: 37280085
pii: 6/8/e202302043
doi: 10.26508/lsa.202302043
pmc: PMC10244618
pii:
doi:
Substances chimiques
Neurofibromin 2
0
Tumor Suppressor Proteins
0
Banques de données
PDB
['4zrj']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund FWF
ID : P 30162
Pays : Austria
Informations de copyright
© 2023 Moesslacher et al.
Références
Oncogene. 2016 Feb 4;35(5):537-48
pubmed: 25893302
Mol Cell. 2021 Oct 21;81(20):4147-4164.e7
pubmed: 34453890
Cancer Res. 2007 Jan 15;67(2):520-7
pubmed: 17234759
Mol Cell Biol. 2010 Jan;30(1):54-67
pubmed: 19884346
J Cell Sci. 1999 Mar;112 ( Pt 6):895-904
pubmed: 10036239
Methods Mol Biol. 2012;812:63-87
pubmed: 22218854
Nat Cell Biol. 2006 Jan;8(1):27-36
pubmed: 16341207
Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99
pubmed: 12154370
Curr Opin Biotechnol. 2020 Jun;63:177-189
pubmed: 32199228
Mol Syst Biol. 2015 Mar 26;11(3):794
pubmed: 25814554
Matrix Biol Plus. 2021 Jul 01;12:100074
pubmed: 34337379
Int J Mol Sci. 2019 Apr 23;20(8):
pubmed: 31018575
Dev Cell. 2001 Jul;1(1):63-72
pubmed: 11703924
Biochem J. 2016 Sep 15;473(18):2763-82
pubmed: 27364155
Oncogene. 2004 Jan 15;23(2):580-7
pubmed: 14724586
J Cell Sci. 2001 May;114(Pt 10):1901-12
pubmed: 11329377
Cell. 1993 Mar 12;72(5):791-800
pubmed: 8453669
Cell Res. 2015 Jul;25(7):801-17
pubmed: 26045165
Microb Cell. 2021 Jul 02;8(8):164-183
pubmed: 34395585
J Cell Biol. 1998 Jun 29;141(7):1589-99
pubmed: 9647651
Nat Commun. 2019 Sep 13;10(1):4162
pubmed: 31519910
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Nucleic Acids Res. 2020 Jan 8;48(D1):D835-D844
pubmed: 31777943
Oncogene. 2019 Sep;38(36):6370-6381
pubmed: 31312020
Nature. 2022 Apr;604(7904):175-183
pubmed: 35388192
Hum Mol Genet. 1998 Feb;7(2):217-26
pubmed: 9425229
J Biol Chem. 2014 May 23;289(21):14674-81
pubmed: 24706749
Oncogene. 2009 Feb 12;28(6):854-65
pubmed: 19029950
Mol Cell Biol. 2011 May;31(10):1983-96
pubmed: 21402777
Curr Opin Chem Biol. 2022 Feb;66:102100
pubmed: 34801969
Lancet. 2009 Jun 6;373(9679):1974-86
pubmed: 19476995
Nature. 1993 Jun 10;363(6429):515-21
pubmed: 8379998
Cell Rep. 2020 Aug 18;32(7):108050
pubmed: 32814053
Oncogene. 1997 Nov 13;15(20):2505-9
pubmed: 9395247
J Neurosci Res. 2000 Nov 15;62(4):491-502
pubmed: 11070492
J Biol Chem. 2001 Mar 9;276(10):7621-9
pubmed: 11106646
Genes Cells. 2014 Aug;19(8):603-19
pubmed: 24912773
Dev Cell. 2012 Apr 17;22(4):703-5
pubmed: 22516197
Nat Commun. 2015 Oct 07;6:8457
pubmed: 26443326
Nature. 2021 Jul;595(7865):120-124
pubmed: 34079125
FEBS Lett. 2014 Aug 19;588(16):2743-52
pubmed: 24726726
Mol Syst Biol. 2022 Mar;18(3):e10820
pubmed: 35225431
J Neurosci Res. 1999 Dec 1;58(5):706-16
pubmed: 10561699
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Genes Dev. 2003 May 1;17(9):1090-100
pubmed: 12695331
J Cell Biol. 2007 Jun 4;177(5):893-903
pubmed: 17548515
Nature. 2018 Oct;562(7726):217-222
pubmed: 30209399
J Mol Biol. 2014 Jul 29;426(15):2755-68
pubmed: 24882693
Cancer Res. 2009 May 1;69(9):4043-51
pubmed: 19351837
Cell. 2010 Feb 19;140(4):477-90
pubmed: 20178741
Biochem Biophys Res Commun. 2002 Jan 11;290(1):366-74
pubmed: 11779178
Nat Methods. 2015 Mar;12(3):203-6, 4 p following 206
pubmed: 25559584
Genes Dev. 1999 Apr 15;13(8):978-86
pubmed: 10215625
Acta Crystallogr D Biol Crystallogr. 2002 Mar;58(Pt 3):381-91
pubmed: 11856822
Orphanet J Rare Dis. 2009 Jun 19;4:16
pubmed: 19545378
Genet Med. 2022 Sep;24(9):1967-1977
pubmed: 35674741
Nat Commun. 2018 Apr 6;9(1):1338
pubmed: 29626191
Cell Syst. 2017 Dec 27;5(6):544-546
pubmed: 29284128
Biochem Biophys Res Commun. 2017 Nov 4;493(1):46-51
pubmed: 28919412
J Biol Chem. 2002 Jan 11;277(2):883-6
pubmed: 11719502
Genetics. 2015 Jun;200(2):413-22
pubmed: 25823446
J Cell Biol. 2005 Oct 24;171(2):361-71
pubmed: 16247032
Oncogene. 1998 Aug 20;17(7):801-10
pubmed: 9779996
Genes Dev. 2001 Apr 15;15(8):968-80
pubmed: 11316791
Nat Methods. 2013 Apr;10(4):339-42
pubmed: 23455924
Oncogene. 2002 Sep 5;21(39):5990-7
pubmed: 12203111
Am J Hum Genet. 2017 Sep 7;101(3):315-325
pubmed: 28886340
J Biol Chem. 2002 Mar 22;277(12):10394-9
pubmed: 11782491
Oncogene. 2008 May 22;27(23):3233-43
pubmed: 18071304
Nat Methods. 2017 Dec;14(12):1213-1221
pubmed: 29039417
J Biol Chem. 2004 Apr 30;279(18):18559-66
pubmed: 14981079
Nat Genet. 2018 Jun;50(6):874-882
pubmed: 29785012
J Cell Sci. 2014 Jan 15;127(Pt 2):267-75
pubmed: 24421310
Mol Cell Biol. 2008 Feb;28(4):1274-84
pubmed: 18086884
Dev Cell. 2010 Jul 20;19(1):27-38
pubmed: 20643348
Cell. 2017 Nov 16;171(5):1029-1041.e21
pubmed: 29056346
Genome Biol. 2019 Nov 4;20(1):223
pubmed: 31679514