Biological regulation via ankyrin repeat folding.

By mimicking the phosphorylation of p19(INK4d), a tumor suppressor containing five ankyrin repeats, the native state could be destabilized to such an extent that only a partially folded state is populated at physiological temperature. This partly folded state, which mimics an on-pathway folding intermediate lacking structure in ankyrin repeats 1 and 2, is more rapidly ubiquitinated than the parent construct. Thus, phosphorylation of p19(INK4d) is likely to regulate cell-cycle progression through both biochemical (proteasomal) and biophysical (folding and binding to cyclin-dependent kinases) mechanisms.