Comparison of molecular dynamics averaged structures for complexes of normal and oncogenic ras-p21 with SOS nucleotide exchange protein, containing computed conformations for three crystallographically undefined domains, suggests a potential role of these domains in ras signaling.
ras-p21 protein binds to the son-of-sevenless (SOS) guanine nucleotide-exchange promoter that allows it to exchange GDP for GTP. Previously, we performed molecular dynamics calculations on oncogenic (Val 12-) and wild-type ras-p21 bound to SOS. By superimposing the average structures of these two complexes, we identified four domains (residues 631-641, 676-691, 718-729, and 994-1004) in SOS that change conformation and were candidates for being effector domains. These calculations were performed in the absence of three crystallographically undefined loops (i.e., residues 591-596, 654-675, and 742-751). We have now modeled these loops into the SOS structure and have re-performed the dynamics calculations. We find that all three loop domains undergo large changes in conformation that involve mostly changes in their positioning and not their individual conformations. We have also identified another potential effector domain (i.e., residues 980-989). Overall, our current results suggest that SOS interactions with oncogenic ras-p21 may enhance ras-p21 mitogenic signaling through prolonging its activation by maintaining its binding to GTP and by allowing its effector domains to interact with intracellular targets.
Duncan
Thomas
T
Department of Biochemistry, SUNY Upstate Medical Center, 750 East Adams Street, Syracuse, NY 13210, USA.
Chen
James M
JM
Friedman
Fred K
FK
Hyde
Mark
M
Chie
Lyndon
L
Pincus
Matthew R
MR
D000818:Animals; D001665:Binding Sites; D006801:Humans; D015689:Oncogene Protein p21(ras) / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020664:Son of Sevenless Proteins / Q000737:chemistry* / Q000378:metabolism
D020664:Son of Sevenless Proteins; D015689:Oncogene Protein p21(ras)