PDBsum entry 3zdt

Transferase

PDB id: 3zdt

Contents

Protein chains

326 a.a.

Waters ×7

PDB id:

3zdt

Name:

Transferase

Title:

Crystal structure of basic patch mutant fak ferm domain fak31- 405 k216a, k218a, r221a, k222a

Structure:

Focal adhesion kinase 1. Chain: a, b. Fragment: ferm domain, residues 31-405. Synonym: fak, fadk 1, focal adhesion kinase-related nonkinase, frnk, p41/p43frnk, protein-tyrosine kinase 2, p125fak, pp125fak. Engineered: yes. Mutation: yes

Source:

Gallus gallus. Chicken. Organism_taxid: 9031. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

3.15Å R-factor: 0.217 R-free: 0.278

Authors:

G.M.Goni,C.Epifano,J.Boskovic,M.Camacho-Artacho,J.Zhou,M.T.Martin, M.J.Eck,L.Kremer,F.Graeter,F.L.Gervasio,M.Perez-Moreno,D.Lietha

Key ref:

G.M.Goñi et al. (2014). Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc Natl Acad Sci U S A, 111, E3177. PubMed id: 25049397 DOI: 10.1073/pnas.1317022111

Date:

30-Nov-12 Release date: 12-Dec-12

Protein chains

Q00944  (FAK1_CHICK) -  Focal adhesion kinase 1 from Gallus gallus

Seq: 1053 a.a.

Struc: 326 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.1317022111

Proc Natl Acad Sci U S A 111:E3177 (2014)

PubMed id: 25049397

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes.

G.M.Goñi, C.Epifano, J.Boskovic, M.Camacho-Artacho, J.Zhou, A.Bronowska, M.T.Martín, M.J.Eck, L.Kremer, F.Gräter, F.L.Gervasio, M.Perez-Moreno, D.Lietha.

ABSTRACT

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type Iγ are important in linking integrin signaling to FAK activation.