Template-based docking of a prolactin receptor proline-rich motif octapeptide to FKBP12: implications for cytokine receptor signaling.
A conserved proline-rich motif (PRM) in the cytoplasmic domain of cytokine receptors has been suggested to be a signaling switch regulated by the action of the FK506 binding protein (FKBP) family of peptidylprolyl isomerases (O'Neal KD, Yu-Lee LY, Shearer WT, 1995, Ann NY Acad Sci 766:282-284). We have docked the prolactin receptor PRM (Ile1-Phe2-Pro3-Pro4-Val5-Pro6-Gly7-Pro8) to the ligand binding site of FKBP12. The procedure involved conformational search restricted by NMR restraints (O'Neal KD et al., 1996, Biochem J 315:833-844), energy minimization of the octapeptide conformers so obtained, template-based docking of a selected conformer to FKBP12, and energy refinement of the resulting complex. The template used was the crystal structure of a cyclic FK506-peptide hybrid bound to FKBP12. Val5-Pro6 of the PRM was taken to be the biologically relevant Xaa-Pro bond. The docked conformer is stabilized by two intramolecular hydrogen bonds, N7H7-->O4 and N2H2-->O8, and two intermolecular ones, Ile56; N-H-->O = C:Pro6 and Tyr82:O-H-->O = C:Gly7. This conformer features a Type I beta-turn and has extensive hydrophobic contacts with the FKBP12 binding surface. The observed interactions support the hypothesis that FKBP12 catalyzes cis-trans isomerization in the PRM when it is part of the longer cytoplasmic domain of a cytokine receptor, and suggest a significant role for the PRM in signal transduction.
Soman
K V
KV
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Hanks
B A
BA
Tien
H
H
Chari
M V
MV
O'Neal
K D
KD
Morrisett
J D
JD
D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011392:Proline; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018121:Receptors, Cytokine / Q000737:chemistry* / Q000502:physiology*; D011981:Receptors, Prolactin / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D016559:Tacrolimus / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D013698:Templates, Genetic
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009842:Oligopeptides; D018121:Receptors, Cytokine; D011981:Receptors, Prolactin; D011392:Proline; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus