ABSTRACT
The p53 homolog TAp63α is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63α is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer that initiates apoptosis. By measuring activation kinetics in ovaries and single-site phosphorylation kinetics in vitro with peptides and full-length protein, we show that TAp63α phosphorylation follows a biphasic behavior. Although the first two CK1 phosphorylation events are fast, the third one, which constitutes the decisive step to form the active conformation, is slow. Structure determination of CK1 in complex with differently phosphorylated peptides reveals the structural mechanism for the difference in the kinetic behavior based on an unusual CK1/TAp63α substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one.
Subject(s)
Apoptosis/physiology , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Catalytic Domain , DNA Damage , Female , Humans , Mice , Models, Molecular , Molecular Dynamics Simulation , Oocytes , Phosphorylation , Protein Conformation , Time Factors , Transcription Factors/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
The absence of vacuum Cherenkov radiation for 104.5 GeV electrons and positrons at the LEP collider at CERN combined with the observed stability of 300 GeV photons at the Tevatron constrains deviations of the speed of light relative to the maximal attainable speed of electrons. Within the standard-model extension, the limit -5.8x10(-12)
ABSTRACT
Within the classical Maxwell-Chern-Simons limit of the standard-model extension, the emission of light by uniformly moving charges is studied confirming the possibility of a Cerenkov-type effect. In this context, the exact radiation rate for charged magnetic point dipoles is determined and found in agreement with a phase-space estimate under certain assumptions.
