The Structural Basis of Localization and Signaling by the Focal Adhesion Targeting Domain

Structure. 2002 Mar;10(3):319-27. doi: 10.1016/s0969-2126(02)00717-7.

Abstract

The localization of focal adhesion kinase (FAK) to sites of integrin clustering initiates downstream signaling. The C-terminal focal adhesion targeting (FAT) domain causes this localization by interacting with talin and paxillin. FAT also mediates signaling through Grb2 via phosphorylated Y925. We report two crystal structures of the FAT domain. Large rearrangements of the structure are indicated to allow phosphorylation of Y925 and subsequent interaction with Grb2. Sequence homology and structural compatibility suggest a FAT-like fold for the C-terminal domains of CAS, Efs/Sin, and HEF1. A structure-based alignment including these proteins and the vinculin tail domain reveals a conserved region that could play a role in focal adhesion targeting. Previously postulated "paxillin binding subdomains" may contribute to structural integrity rather than directly to paxillin binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Adhesion / physiology
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / metabolism
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • GRB2 Adaptor Protein
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Paxillin
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary*
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism
  • Sequence Alignment
  • Signal Transduction / physiology*
  • Tyrosine / metabolism
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • PXN protein, human
  • Paxillin
  • Phosphoproteins
  • Proteins
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human

Associated data

  • PDB/1K04
  • PDB/1K05