Oncogenic mutations and packing defects in protein structure.
Oncogenic mutations in expressed proteins are of primary interest to understand tumor formation but their structural consequences bearing on protein function are not clearly understood. In this contribution I report on two illustrative examples, p21ras and p57, revealing that such mutations have an effect on specific structural deficiencies in the packing of the protein structure, i. e., on backbone hydrogen bonds insufficiently shielded from water attack. These structural deficiencies in the wild type are typically "corrected intermolecularly" by protein complexation or protein-ligand association. However, in the oncogenic mutants, these binding signals are partially or completely suppressed: the mutated residues properly wrap or desolvate the hydrogen bonds intramolecularly. Thus, the interactivity of the proteins becomes impaired: their binding affinity decreases sharply, as there is no thermodynamic benefit from removing water surrounding properly desolvated hydrogen bonds. The results, specialized for p21ras and p53, reveal how oncogenic mutations determine a hindrance to GAP-induced hydrolysis (p21) and decrease binding affinity for DNA (p53). Furthermore, the oncogenic potential of mutations in residues not directly engaged in the interface electrostatics is assessed. The results suggest that a high sensitivity of structural defects to genetic accident might be a necessary condition to establish the existence of a proto-oncogene, an angle that merits a systematic study.
Fernández
Ariel
A
Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA. ariel@uchicago.edu
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D001665:Binding Sites; D005998:Glycine / Q000235:genetics; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014633:Valine / Q000235:genetics
D008024:Ligands; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D016283:Proto-Oncogene Proteins p21(ras); D014633:Valine; D000409:Alanine; D005998:Glycine