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Title: Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase

Abstract

The LIM-only adaptor PINCH (the particularly interesting cysteine- and histidine-rich protein) plays a pivotal role in the assembly of focal adhesions (FAs), supramolecular complexes that transmit mechanical and biochemical information between extracellular matrix and actin cytoskeleton, regulating diverse cell adhesive processes such as cell migration, cell spreading, and survival. A key step for the PINCH function is its localization to FAs, which depends critically on the tight binding of PINCH to integrin-linked kinase (ILK). Here we report the solution NMR structure of the core ILK {center_dot} PINCH complex (28 kDa, K{sub D} {approx} 68 nm) involving the N-terminal ankyrin repeat domain (ARD) of ILK and the first LIM domain (LIM1) of PINCH. We show that the ILK ARD exhibits five sequentially stacked ankyrin repeat units, which provide a large concave surface to grip the two contiguous zinc fingers of the PINCH LIM1. The highly electrostatic interface is evolutionally conserved but differs drastically from those of known ARD and LIM bound to other types of protein domains. Consistently mutation of a hot spot in LIM1, which is not conserved in other LIM domains, disrupted the PINCH binding to ILK and abolished the PINCH targeting to FAs. These data provide atomic insightmore » into a novel modular recognition and demonstrate how PINCH is specifically recruited by ILK to mediate the FA assembly and cell-extracellular matrix communication.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006206
Resource Type:
Journal Article
Journal Name:
J. Biol. Chem.
Additional Journal Information:
Journal Volume: 284; Journal Issue: 02, 2009; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ACTIN; ADHESION; ADHESIVES; CYSTEINE; ELECTROSTATICS; FINGERS; HOT SPOTS; MUTATIONS; PHOSPHOTRANSFERASES; PROTEINS; ZINC

Citation Formats

Yang, Yanwu, Wang, Xiaoxia, Hawkins, Cheryl A, Chen, Kan, Vaynberg, Julia, Mao, Xian, Tu, Yizeng, Zuo, Xiaobing, Wang, Jinbu, Wang, Yun-xing, Wu, Chuanyue, Tjandra, Nico, Qin, Jun, Pitt), Cleveland Clinic), and NIH). Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase. United States: N. p., 2010. Web. doi:10.1074/jbc.M805319200.
Yang, Yanwu, Wang, Xiaoxia, Hawkins, Cheryl A, Chen, Kan, Vaynberg, Julia, Mao, Xian, Tu, Yizeng, Zuo, Xiaobing, Wang, Jinbu, Wang, Yun-xing, Wu, Chuanyue, Tjandra, Nico, Qin, Jun, Pitt), Cleveland Clinic), & NIH). Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase. United States. doi:10.1074/jbc.M805319200.
Yang, Yanwu, Wang, Xiaoxia, Hawkins, Cheryl A, Chen, Kan, Vaynberg, Julia, Mao, Xian, Tu, Yizeng, Zuo, Xiaobing, Wang, Jinbu, Wang, Yun-xing, Wu, Chuanyue, Tjandra, Nico, Qin, Jun, Pitt), Cleveland Clinic), and NIH). Mon . "Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase". United States. doi:10.1074/jbc.M805319200.
@article{osti_1006206,
title = {Structural Basis of Focal Adhesion Localization of LIM-only Adaptor PINCH by Integrin-linked Kinase},
author = {Yang, Yanwu and Wang, Xiaoxia and Hawkins, Cheryl A and Chen, Kan and Vaynberg, Julia and Mao, Xian and Tu, Yizeng and Zuo, Xiaobing and Wang, Jinbu and Wang, Yun-xing and Wu, Chuanyue and Tjandra, Nico and Qin, Jun and Pitt) and Cleveland Clinic) and NIH)},
abstractNote = {The LIM-only adaptor PINCH (the particularly interesting cysteine- and histidine-rich protein) plays a pivotal role in the assembly of focal adhesions (FAs), supramolecular complexes that transmit mechanical and biochemical information between extracellular matrix and actin cytoskeleton, regulating diverse cell adhesive processes such as cell migration, cell spreading, and survival. A key step for the PINCH function is its localization to FAs, which depends critically on the tight binding of PINCH to integrin-linked kinase (ILK). Here we report the solution NMR structure of the core ILK {center_dot} PINCH complex (28 kDa, K{sub D} {approx} 68 nm) involving the N-terminal ankyrin repeat domain (ARD) of ILK and the first LIM domain (LIM1) of PINCH. We show that the ILK ARD exhibits five sequentially stacked ankyrin repeat units, which provide a large concave surface to grip the two contiguous zinc fingers of the PINCH LIM1. The highly electrostatic interface is evolutionally conserved but differs drastically from those of known ARD and LIM bound to other types of protein domains. Consistently mutation of a hot spot in LIM1, which is not conserved in other LIM domains, disrupted the PINCH binding to ILK and abolished the PINCH targeting to FAs. These data provide atomic insight into a novel modular recognition and demonstrate how PINCH is specifically recruited by ILK to mediate the FA assembly and cell-extracellular matrix communication.},
doi = {10.1074/jbc.M805319200},
journal = {J. Biol. Chem.},
issn = {0021-9258},
number = 02, 2009,
volume = 284,
place = {United States},
year = {2010},
month = {11}
}