Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
20
08
2021
revised:
21
12
2021
accepted:
28
01
2022
pubmed:
6
2
2022
medline:
15
4
2022
entrez:
5
2
2022
Statut:
ppublish
Résumé
Cellular mechanosensing is pivotal for virtually all biological processes, and many molecular mechano-sensors and their way of function are being uncovered. In this work, we suggest that c-Src kinase acts as a direct mechano-sensor. c-Src is responsible for, among others, cell proliferation, and shows increased activity in stretched cells. In its native state, c-Src has little basal activity, because its kinase domain binds to an SH2 and SH3 domain. However, it is known that c-Src can bind to p130Cas, through which force can be transmitted to the membrane. Using molecular dynamics simulations, we show that force acting between the membrane-bound N-terminus of the SH3 domain and p130Cas induces partial SH3 unfolding, thereby impeding rebinding of the kinase domain onto SH2/SH3 and effectively enhancing kinase activity. Forces involved in this process are slightly lower or similar to the forces required to pull out c-Src from the membrane through the myristoyl linker, and key interactions involved in this anchoring are salt bridges between negative lipids and nearby basic residues in c-Src. Thus, c-Src appears to be a candidate for an intriguing mechanosensing mechanism of impaired kinase inhibition, which can be potentially tuned by membrane composition and other environmental factors.
Identifiants
pubmed: 35120901
pii: S0006-3495(22)00078-9
doi: 10.1016/j.bpj.2022.01.028
pmc: PMC8943751
pii:
doi:
Substances chimiques
Protein-Tyrosine Kinases
EC 2.7.10.1
CSK Tyrosine-Protein Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
684-691Informations de copyright
Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Références
Biophys J. 2002 Jun;82(6):3343-50
pubmed: 12023256
Methods Mol Biol. 2005;305:493-515
pubmed: 15943012
Mol Cell Biol. 2008 Jan;28(1):201-14
pubmed: 17967873
Nature. 2001 May 17;411(6835):355-65
pubmed: 11357143
Elife. 2018 Jul 19;7:
pubmed: 30024850
J Comput Chem. 2008 Aug;29(11):1859-65
pubmed: 18351591
Oncogene. 2004 Oct 18;23(48):7906-9
pubmed: 15489908
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13385-90
pubmed: 18765796
Cell. 2006 Dec 1;127(5):1015-26
pubmed: 17129785
J Chem Phys. 2004 Apr 1;120(13):5946-61
pubmed: 15267476
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E8977-E8986
pubmed: 29073094
J Comput Chem. 2005 Dec;26(16):1701-18
pubmed: 16211538
Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9193-8
pubmed: 27482115
Biochim Biophys Acta. 2005 Dec 30;1754(1-2):210-20
pubmed: 16198159
J Phys Chem B. 2017 Apr 20;121(15):3352-3363
pubmed: 27715044
Acc Chem Res. 2017 May 16;50(5):1193-1201
pubmed: 28426203
J Phys Chem B. 2019 May 2;123(17):3658-3664
pubmed: 30970209
Nature. 2005 Apr 21;434(7036):1040-5
pubmed: 15846350
J Biol Chem. 1993 Aug 25;268(24):18070-5
pubmed: 7688738
J Mol Recognit. 2006 Jan-Feb;19(1):30-8
pubmed: 16245368
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Biophys J. 2018 Mar 27;114(6):1267-1273
pubmed: 29590584
J Biol Chem. 2004 Dec 24;279(52):54793-801
pubmed: 15485829
PLoS One. 2015 Jul 17;10(7):e0132833
pubmed: 26186725
J Mol Biol. 1993 Dec 5;234(3):779-815
pubmed: 8254673
J Mol Biol. 2014 Jan 23;426(2):423-35
pubmed: 24103328
J Phys Chem B. 2008 Jul 31;112(30):9020-41
pubmed: 18593145
Mol Cell. 1999 May;3(5):629-38
pubmed: 10360179
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12253-7
pubmed: 7527558
Nat Commun. 2014 Mar 03;5:3397
pubmed: 24584478
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6766-6774
pubmed: 30877242
J Am Chem Soc. 2019 Sep 25;141(38):15092-15101
pubmed: 31476863
Biophys J. 2005 Feb;88(2):790-804
pubmed: 15531631
Trends Cell Biol. 2006 May;16(5):257-63
pubmed: 16581250
PLoS Comput Biol. 2015 Nov 06;11(11):e1004593
pubmed: 26544178
J Comput Chem. 2013 Sep 30;34(25):2135-45
pubmed: 23832629
J Chem Phys. 2007 Jan 7;126(1):014101
pubmed: 17212484
Sci Rep. 2018 Apr 4;8(1):5673
pubmed: 29618744
Proteins. 2010 Jun;78(8):1950-8
pubmed: 20408171
Protein Sci. 2006 Jan;15(1):65-73
pubmed: 16322569
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13298-302
pubmed: 14593208