Complex Structures of Rsu1 and PINCH1 Reveal a Regulatory Mechanism of the ILK/PINCH/Parvin Complex for F-actin Dynamics

Overview

Journal Elife

Specialty Biology

Date 2021 Feb 15

PMID 33587032

Citations 5

Authors

Haibin Yang

Leishu Lin

Kang Sun

Ting Zhang

Wan Chen

Lianghui Li

Yuchen Xie

Chuanyue Wu

Zhiyi Wei

Cong Yu

Affiliations

Soon will be listed here.

Abstract

Communications between actin filaments and integrin-mediated focal adhesion (FA) are crucial for cell adhesion and migration. As a core platform to organize FA proteins, the tripartite ILK/PINCH/Parvin (IPP) complex interacts with actin filaments to regulate the cytoskeleton-FA crosstalk. Rsu1, a Ras suppressor, is enriched in FA through PINCH1 and plays important roles in regulating F-actin structures. Here, we solved crystal structures of the Rsu1/PINCH1 complex, in which the leucine-rich-repeats of Rsu1 form a solenoid structure to tightly associate with the C-terminal region of PINCH1. Further structural analysis uncovered that the interaction between Rsu1 and PINCH1 blocks the IPP-mediated F-actin bundling by disrupting the binding of PINCH1 to actin. Consistently, overexpressing Rsu1 in HeLa cells impairs stress fiber formation and cell spreading. Together, our findings demonstrated that Rsu1 is critical for tuning the communication between F-actin and FA by interacting with the IPP complex and negatively modulating the F-actin bundling.

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References

Cabodi S, Camacho-Leal M, Di Stefano P, Defilippi P . Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer. 2010; 10(12):858-70. DOI: 10.1038/nrc2967. View

Stiegler A, Draheim K, Li X, Chayen N, Calderwood D, Boggon T . Structural basis for paxillin binding and focal adhesion targeting of β-parvin. J Biol Chem. 2012; 287(39):32566-77. PMC: 3463362. DOI: 10.1074/jbc.M112.367342. View

Dougherty G, Jose C, Gimona M, Cutler M . The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells. Eur J Cell Biol. 2008; 87(8-9):721-34. PMC: 2600675. DOI: 10.1016/j.ejcb.2008.02.011. View

Zacharia L, Stylianopoulos T, Gkretsi V . Ras Suppressor-1 (RSU-1) in Cancer Cell Metastasis: Friend or Foe?. Crit Rev Oncog. 2018; 22(3-4):249-253. PMC: 5985951. DOI: 10.1615/CritRevOncog.2018024231. View

Wang X, Huang S, Zheng C, Ge W, Wu C, Tse Y . RSU-1 Maintains Integrity of Vulval Muscles by Regulating α-Actinin. G3 (Bethesda). 2020; 10(7):2507-2517. PMC: 7341117. DOI: 10.1534/g3.120.401185. View

Horton E, Byron A, Askari J, Ng D, Millon-Fremillon A, Robertson J . Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat Cell Biol. 2015; 17(12):1577-1587. PMC: 4663675. DOI: 10.1038/ncb3257. View

Green H, Griffiths A, Ylanne J, Brown N . Novel functions for integrin-associated proteins revealed by analysis of myofibril attachment in . Elife. 2018; 7. PMC: 6092120. DOI: 10.7554/eLife.35783. View

Winograd-Katz S, Itzkovitz S, Kam Z, Geiger B . Multiparametric analysis of focal adhesion formation by RNAi-mediated gene knockdown. J Cell Biol. 2009; 186(3):423-36. PMC: 2728402. DOI: 10.1083/jcb.200901105. View

Adams P, Afonine P, Bunkoczi G, Chen V, Davis I, Echols N . PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 2):213-21. PMC: 2815670. DOI: 10.1107/S0907444909052925. View

10.

Storoni L, McCoy A, Read R . Likelihood-enhanced fast rotation functions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 3):432-8. DOI: 10.1107/S0907444903028956. View

11.

Calderwood D, Shattil S, Ginsberg M . Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J Biol Chem. 2000; 275(30):22607-10. DOI: 10.1074/jbc.R900037199. View

12.

Montanez E, Karakose E, Tischner D, Villunger A, Fassler R . PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm. J Cell Sci. 2012; 125(Pt 21):5233-40. DOI: 10.1242/jcs.112029. View

13.

Dougherty G, Chopp T, Qi S, Cutler M . The Ras suppressor Rsu-1 binds to the LIM 5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions. Exp Cell Res. 2005; 306(1):168-79. DOI: 10.1016/j.yexcr.2005.01.025. View

14.

Gkretsi V, Kalli M, Efstathiades C, Papageorgis P, Papanikolaou V, Zacharia L . Depletion of Ras Suppressor-1 (RSU-1) promotes cell invasion of breast cancer cells through a compensatory upregulation of a truncated isoform. Sci Rep. 2019; 9(1):10050. PMC: 6624310. DOI: 10.1038/s41598-019-46575-0. View

15.

Fukuda K, Bledzka K, Yang J, Perera H, Plow E, Qin J . Molecular basis of kindlin-2 binding to integrin-linked kinase pseudokinase for regulating cell adhesion. J Biol Chem. 2014; 289(41):28363-75. PMC: 4192489. DOI: 10.1074/jbc.M114.596692. View

16.

Geiger B, Bershadsky A, Pankov R, Yamada K . Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk. Nat Rev Mol Cell Biol. 2001; 2(11):793-805. DOI: 10.1038/35099066. View

17.

Legate K, Montanez E, Kudlacek O, Fassler R . ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol. 2006; 7(1):20-31. DOI: 10.1038/nrm1789. View

18.

Davis I, Leaver-Fay A, Chen V, Block J, Kapral G, Wang X . MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res. 2007; 35(Web Server issue):W375-83. PMC: 1933162. DOI: 10.1093/nar/gkm216. View

19.

Kadrmas J, Smith M, Clark K, Pronovost S, Muster N, Yates 3rd J . The integrin effector PINCH regulates JNK activity and epithelial migration in concert with Ras suppressor 1. J Cell Biol. 2004; 167(6):1019-24. PMC: 2034365. DOI: 10.1083/jcb.200408090. View

20.

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View