Molecular basis for phosphorylation dependent PEST mediated protein turnover.

GARCÍA ALAI, M.; GALLO, M.; SALAME, M.; WETZLER, D.; MCBRIDE, A.; CICERO, D.; PACI, M.; PRAT GAY, G. DE

STRUCTURE WITH FOLDING & DESIGN.

Año: 2006 vol. 14 p. 309 - 319

0969-2126

Summary Proteasomal-mediated rapid turnover of proteins is often modulated by phosphorylation of PEST sequences. The E2 protein from papillomavirus participates in gene transcription, DNA replication, and episomal genome maintenance. Phosphorylation of a PEST sequence located in a flexible region accelerates its degradation. NMR analysis of a 29 amino acid peptide fragment derived from this region shows pHdependent polyproline II and a helix structures, connected by a turn. Phosphorylation, in particular that at serine 301, disrupts the overall structure, and point mutations have either stabilizing or destabilizing effects. There is an excellent correlation between the thermodynamic stability of different peptides and the half-life of E2 proteins containing the same mutations in vivo. The structure around the PEST region appears to have evolved a marginal stability that is finely tunable by phosphorylation. Thus, conformational stability, rather than recognition of a phosphate modification, modulates the degradation of thisPESTsequence by the proteasome machinery.