Inhibition of oncogenic and activated wild-type ras-p21 protein-induced oocyte maturation by peptides from the guanine-nucleotide exchange protein, SOS, identified from molecular dynamics calculations. Selective inhibition of oncogenic ras-p21.
In the preceding paper we performed molecular dynamics calculations of the average structures of the SOS protein bound to wild-type and oncogenic ras-p21. Based on these calculations, we have identified four major domains of the SOS protein, consisting of residues 631-641, 676-691, 718-729, and 994-1004, which differ in structure between the two complexes. We have now microinjected synthetic peptides corresponding to each of these domains into Xenopus laevis oocytes either together with oncogenic (Val 12)-p21 or into oocytes subsequently incubated with insulin. We find that the first three peptides inhibit both oncogenic and wild-type p21-induced oocyte maturation, while the last peptide much more strongly inhibits oncogenic p21 protein-induced oocyte maturation. These results suggest that each identified SOS region is involved in ras-stimulated signal transduction and that the 994-1004 domain is involved uniquely with oncogenic ras-p21 signaling.
Chie
L
L
Department of Pathology and Laboratory Medicine, Harbor VA Medical Center, Brooklyn, New York 11209, USA.
Chen
J M
JM
Friedman
F K
FK
Chung
D L
DL
Amar
S
S
Michl
J
J
Yamaizumi
Z
Z
Brandt-Rauf
P W
PW
Pincus
M R
MR
D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D020664:Son of Sevenless Proteins / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors
D007328:Insulin; D010446:Peptide Fragments; D020664:Son of Sevenless Proteins; D015689:Oncogene Protein p21(ras)