Structural differences between a ras oncogene protein and the normal protein.
One of the most commonly found transforming ras oncogenes in human tumours has a valine codon replacing the glycine codon at position 12 of the normal c-Ha-ras gene. To understand the structural reasons behind cell transformation arising from this single amino acid substitution, we have determined the crystal structure of the GDP-bound form of the mutant protein, p21(Val-12), encoded by this oncogene. We report here the overall structure of p21(Val-12) at 2.2 A resolution and compare it with the structure of the normal c-Ha-ras protein. One of the major differences is that the loop of the transforming ras protein that binds the beta-phosphate of the guanine nucleotide is enlarged. Such a change in the 'catalytic site' conformation could explain the reduced GTPase activity of the mutant, which keeps the protein in the GTP bound 'signal on' state for a prolonged period time, ultimately causing cell transformation.
Tong
L A
LA
Department of Chemistry, University of California, Berkeley 94720.
de Vos
A M
AM
Milburn
M V
MV
Jancarik
J
J
Noguchi
S
S
Nishimura
S
S
Miura
K
K
Ohtsuka
E
E
Kim
S H
SH
D003461:Crystallography; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009690:Nucleic Acid Conformation; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras)
D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras)