skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural Basis of Competition Between PINCH1 and PINCH2 for Binding to the Ankyrin Repeat Domain of Integrin-linked Kinase

Abstract

Formation of a heterotrimeric IPP complex composed of integrin-linked kinase (ILK), the LIM domain protein PINCH, and parvin is important for signaling through integrin adhesion receptors. Mammals possess two PINCH genes that are expressed simultaneously in many tissues. PINCH1 and PINCH2 have overlapping functions and can compensate for one another in many settings; however, isoform-specific functions have been reported and it is proposed that association with a PINCH1- or PINCH2-containing IPP complex may provide a bifurcation point in integrin signaling promoting different cellular responses. Here we report that the LIM1 domains of PINCH1 and PINCH2 directly compete for the same binding site on the ankyrin repeat domain (ARD) of ILK. We determined the 1.9 {angstrom} crystal structure of the PINCH2 LIM1 domain complexed with the ARD of ILK, and show that disruption of this interface by point mutagenesis reduces binding in vitro and alters localization of PINCH2 in cells. These studies provide further evidence for the role of the PINCH LIM1 domain in association with ILK and highlight direct competition as one mechanism for regulating which PINCH isoform predominates in IPP complexes. Differential regulation of PINCH1 and PINCH2 expression may therefore provide a means for altering cellular integrin signaling pathways.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
DOE - OFFICE OF SCIENCE
OSTI Identifier:
1019953
Report Number(s):
BNL-95799-2011-JA
Journal ID: ISSN 1047-8477; JSBIEM; TRN: US201115%%589
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of Structural Biology
Additional Journal Information:
Journal Volume: 170; Journal Issue: 1; Journal ID: ISSN 1047-8477
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ADHESION; BIFURCATION; CRYSTAL STRUCTURE; GENES; IN VITRO; MAMMALS; MUTAGENESIS; PHOSPHOTRANSFERASES; PROTEINS; REGULATIONS; national synchrotron light source

Citation Formats

Chiswell, B, Steigler, A, Razinia, Z, Nalibotski, E, Boggon, T, and Calderwood, D. Structural Basis of Competition Between PINCH1 and PINCH2 for Binding to the Ankyrin Repeat Domain of Integrin-linked Kinase. United States: N. p., 2010. Web. doi:10.1016/j.jsb.2009.12.002.
Chiswell, B, Steigler, A, Razinia, Z, Nalibotski, E, Boggon, T, & Calderwood, D. Structural Basis of Competition Between PINCH1 and PINCH2 for Binding to the Ankyrin Repeat Domain of Integrin-linked Kinase. United States. doi:10.1016/j.jsb.2009.12.002.
Chiswell, B, Steigler, A, Razinia, Z, Nalibotski, E, Boggon, T, and Calderwood, D. Fri . "Structural Basis of Competition Between PINCH1 and PINCH2 for Binding to the Ankyrin Repeat Domain of Integrin-linked Kinase". United States. doi:10.1016/j.jsb.2009.12.002.
@article{osti_1019953,
title = {Structural Basis of Competition Between PINCH1 and PINCH2 for Binding to the Ankyrin Repeat Domain of Integrin-linked Kinase},
author = {Chiswell, B and Steigler, A and Razinia, Z and Nalibotski, E and Boggon, T and Calderwood, D},
abstractNote = {Formation of a heterotrimeric IPP complex composed of integrin-linked kinase (ILK), the LIM domain protein PINCH, and parvin is important for signaling through integrin adhesion receptors. Mammals possess two PINCH genes that are expressed simultaneously in many tissues. PINCH1 and PINCH2 have overlapping functions and can compensate for one another in many settings; however, isoform-specific functions have been reported and it is proposed that association with a PINCH1- or PINCH2-containing IPP complex may provide a bifurcation point in integrin signaling promoting different cellular responses. Here we report that the LIM1 domains of PINCH1 and PINCH2 directly compete for the same binding site on the ankyrin repeat domain (ARD) of ILK. We determined the 1.9 {angstrom} crystal structure of the PINCH2 LIM1 domain complexed with the ARD of ILK, and show that disruption of this interface by point mutagenesis reduces binding in vitro and alters localization of PINCH2 in cells. These studies provide further evidence for the role of the PINCH LIM1 domain in association with ILK and highlight direct competition as one mechanism for regulating which PINCH isoform predominates in IPP complexes. Differential regulation of PINCH1 and PINCH2 expression may therefore provide a means for altering cellular integrin signaling pathways.},
doi = {10.1016/j.jsb.2009.12.002},
journal = {Journal of Structural Biology},
issn = {1047-8477},
number = 1,
volume = 170,
place = {United States},
year = {2010},
month = {1}
}