Computed three-dimensional structures for the ras-binding domain of the raf-p74 protein complexed with ras-p21 and with its suppressor protein, rap-1A.
The three-dimensional structures of the ras-p21 protein and its protein inhibitor, rap-1A, have been computed bound to the ras-binding domain, RBD (residues 55-131), of the raf-p74 protein, a critical target protein of ras-p21 in the ras-induced mitogenic signal transduction pathway. The coordinates of RBD have been reconstructed from the stereoview of an X-ray crystal structure of this domain bound to rap-1A and have been subjected to energy minimization. The energy-minimized structures of both ras-p21 and rap-1A, obtained in previous studies, have been docked against RBD, using the stereo figure of the RBD-rap-1A complex, based on a six-step procedure. The final energy-minimized structure of rap-1A-RBD is identical to the X-ray crystal structure. Comparison of the ras-p21- and rap-1A-RBD complexes reveals differences in the structures of effector domains of ras-p21 and rap-1a, including residues 32-47, a domain that directly interacts with RBD, 60-66, 96-110, involved in the interaction of ras-p21 with jun kinase (JNK) and jun protein, and 115-126, involved in the interaction of p21 with JNK. The structure of the RBD remained the same in both complexes with the exception of small deviations in its beta-2 binding loop (residues 63-71) and residues 89-91, also involved in binding to rap-1A. The results suggest that the binding of these two proteins to RBD may allow them to interact with other cellular target proteins such as JNK and jun.
Chen
J M
JM
Dupont Agricultural Products, Stein-Haskell Research Center, Newark, Delaware 19714, USA.
Manolatos
S
S
Brandt-Rauf
P W
PW
Murphy
R B
RB
Monaco
R
R
Pincus
M R
MR
D019204:GTP-Binding Proteins / Q000737:chemistry*; D015689:Oncogene Protein p21(ras) / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D019908:Proto-Oncogene Proteins c-raf; D020668:rap GTP-Binding Proteins
D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019204:GTP-Binding Proteins; D015689:Oncogene Protein p21(ras); D020668:rap GTP-Binding Proteins