The molecular basis of filamin binding to integrins and competition with talin

Tiila Kiema, Yatish Lad, Pengju Jiang, Camilla L Oxley, Massimiliano Baldassarre, Kate L Wegener, Iain D Campbell, Jari Ylänne, David A Calderwood

Research output: Contribution to journalArticle

271 Citations (Scopus)

Abstract

The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.

Original languageEnglish
Pages (from-to)337-47
Number of pages11
JournalMolecular Cell
Volume21
Issue number3
DOIs
Publication statusPublished - 3 Feb 2006

Fingerprint

Filamins
Talin
Integrins
Phosphothreonine
Integrin beta Chains
Cytoskeleton
Actin Cytoskeleton
Protein Binding
Actins
Proteins
Phosphotransferases
Binding Sites
Cell Membrane
Mutation

Keywords

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calpain
  • Contractile Proteins
  • Crystallography, X-Ray
  • Filamins
  • Integrin beta Chains
  • Mice
  • Microfilament Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins
  • Reproducibility of Results
  • Sequence Homology, Amino Acid
  • Talin

Cite this

Kiema, T., Lad, Y., Jiang, P., Oxley, C. L., Baldassarre, M., Wegener, K. L., ... Calderwood, D. A. (2006). The molecular basis of filamin binding to integrins and competition with talin. Molecular Cell, 21(3), 337-47. https://doi.org/10.1016/j.molcel.2006.01.011

The molecular basis of filamin binding to integrins and competition with talin. / Kiema, Tiila; Lad, Yatish; Jiang, Pengju; Oxley, Camilla L; Baldassarre, Massimiliano; Wegener, Kate L; Campbell, Iain D; Ylänne, Jari; Calderwood, David A.

In: Molecular Cell, Vol. 21, No. 3, 03.02.2006, p. 337-47.

Research output: Contribution to journalArticle

Kiema, T, Lad, Y, Jiang, P, Oxley, CL, Baldassarre, M, Wegener, KL, Campbell, ID, Ylänne, J & Calderwood, DA 2006, 'The molecular basis of filamin binding to integrins and competition with talin', Molecular Cell, vol. 21, no. 3, pp. 337-47. https://doi.org/10.1016/j.molcel.2006.01.011
Kiema, Tiila ; Lad, Yatish ; Jiang, Pengju ; Oxley, Camilla L ; Baldassarre, Massimiliano ; Wegener, Kate L ; Campbell, Iain D ; Ylänne, Jari ; Calderwood, David A. / The molecular basis of filamin binding to integrins and competition with talin. In: Molecular Cell. 2006 ; Vol. 21, No. 3. pp. 337-47.
@article{8594dbbffc3641e88d53515ffcd484d1,
title = "The molecular basis of filamin binding to integrins and competition with talin",
abstract = "The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.",
keywords = "Amino Acid Sequence, Animals, Binding Sites, Calpain, Contractile Proteins, Crystallography, X-Ray, Filamins, Integrin beta Chains, Mice, Microfilament Proteins, Models, Molecular, Molecular Sequence Data, NIH 3T3 Cells, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Recombinant Fusion Proteins, Reproducibility of Results, Sequence Homology, Amino Acid, Talin",
author = "Tiila Kiema and Yatish Lad and Pengju Jiang and Oxley, {Camilla L} and Massimiliano Baldassarre and Wegener, {Kate L} and Campbell, {Iain D} and Jari Yl{\"a}nne and Calderwood, {David A}",
year = "2006",
month = "2",
day = "3",
doi = "10.1016/j.molcel.2006.01.011",
language = "English",
volume = "21",
pages = "337--47",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - The molecular basis of filamin binding to integrins and competition with talin

AU - Kiema, Tiila

AU - Lad, Yatish

AU - Jiang, Pengju

AU - Oxley, Camilla L

AU - Baldassarre, Massimiliano

AU - Wegener, Kate L

AU - Campbell, Iain D

AU - Ylänne, Jari

AU - Calderwood, David A

PY - 2006/2/3

Y1 - 2006/2/3

N2 - The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.

AB - The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.

KW - Amino Acid Sequence

KW - Animals

KW - Binding Sites

KW - Calpain

KW - Contractile Proteins

KW - Crystallography, X-Ray

KW - Filamins

KW - Integrin beta Chains

KW - Mice

KW - Microfilament Proteins

KW - Models, Molecular

KW - Molecular Sequence Data

KW - NIH 3T3 Cells

KW - Nuclear Magnetic Resonance, Biomolecular

KW - Protein Binding

KW - Protein Conformation

KW - Protein Structure, Tertiary

KW - Recombinant Fusion Proteins

KW - Reproducibility of Results

KW - Sequence Homology, Amino Acid

KW - Talin

U2 - 10.1016/j.molcel.2006.01.011

DO - 10.1016/j.molcel.2006.01.011

M3 - Article

C2 - 16455489

VL - 21

SP - 337

EP - 347

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -