Predicted nucleotide-binding properties of p21 protein and its cancer-associated variant

Recently, it has been demonstrated that a single point mutation is responsible for the acquisition of transforming properties by the EJ and T24 human bladder carcinoma gene1–3. The point mutation consists of the conversion of guanine into thymine, which results in the replacement of a glycine by a valine at position 12 of the p21 protein encoded by the EJ and T24 genes. Sequence data of retroviral analogues of the p21 protein1–5 also indicate the importance for a glycine residue at position 12 in normal p21. Comparison of the sequence of the 37 N-terminal residues of the normal human p21 protein with the sequence of the dinucleotide-binding βαβ unit in a group of structurally related enzymes, suggests that these residues of p21 fold into a very similar unit which is also involved in binding a nucleotide. We present here a three-dimensional model of the p21 βαβ unit which explains directly why glycine at position 12 cannot be replaced by another residue without altering the nucleotide-binding properties of p21.