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.
Dupont Agricultural Products, Stein-Haskell Research Center, Newark, Delaware 19714, USA.
J M
JM
Chen
S
S
Manolatos
P W
PW
Brandt-Rauf
R B
RB
Murphy
R
R
Monaco
M R
MR
Pincus
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