Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases.
Sci Signal
; 8(405): rs13, 2015 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-26628682
ABSTRACT
Protein kinase autophosphorylation is a common regulatory mechanism in cell signaling pathways. Crystal structures of several homomeric protein kinase complexes have a serine, threonine, or tyrosine autophosphorylation site of one kinase monomer located in the active site of another monomer, a structural complex that we call an "autophosphorylation complex." We developed and applied a structural bioinformatics method to identify all such autophosphorylation complexes in x-ray crystallographic structures in the Protein Data Bank (PDB). We identified 15 autophosphorylation complexes in the PDB, of which five complexes had not previously been described in the publications describing the crystal structures. These five complexes consist of tyrosine residues in the N-terminal juxtamembrane regions of colony-stimulating factor 1 receptor (CSF1R, Tyr(561)) and ephrin receptor A2 (EPHA2, Tyr(594)), tyrosine residues in the activation loops of the SRC kinase family member LCK (Tyr(394)) and insulin-like growth factor 1 receptor (IGF1R, Tyr(1166)), and a serine in a nuclear localization signal region of CDC-like kinase 2 (CLK2, Ser(142)). Mutations in the complex interface may alter autophosphorylation activity and contribute to disease; therefore, we mutated residues in the autophosphorylation complex interface of LCK and found that two mutations impaired autophosphorylation (T445V and N446A) and mutation of Pro(447) to Ala, Gly, or Leu increased autophosphorylation. The identified autophosphorylation sites are conserved in many kinases, suggesting that, by homology, these complexes may provide insight into autophosphorylation complex interfaces of kinases that are relevant drug targets.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Protein Serine-Threonine Kinases
/
Receptor, Macrophage Colony-Stimulating Factor
/
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
/
Databases, Protein
/
Receptor, EphA2
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Sci Signal
Journal subject:
CIENCIA
/
FISIOLOGIA
Year:
2015
Document type:
Article
Affiliation country:
United States