Current research projects
Proteins are not static structures but constantly fluctuate in conformation on many different timescales because of thermal energy, thereby accessing structural motifs that can be distinct from the native structure. We aim to understand the functional role of these fluctuations in two areas of biophysics: (A) the mammalian circadian clock and (B) metamorphic proteins.
(A) The mammalian circadian clock
Circadian rhythms are endogenous oscillations that function through a network of tightly regulated protein-protein and protein-DNA interactions to synchronize biochemical and behavioural events of an organism to the 24 h day-night cycle. Circadian timekeeping, which has been recognized in the 2017 Nobel Prize for Physiology or Medicine, offers a selective advantage to organisms by enabling them to anticipate and adapt to the day-night cycle. Disruption of this synchrony because of ever-increasing shift work, as well as widespread exposure to low levels of light at night, has been linked to diverse disorders such as cardiovascular disease and cancer.
Circadian rhythms are endogenous oscillations that function through a network of tightly regulated protein-protein and protein-DNA interactions to synchronize biochemical and behavioural events of an organism to the 24 h day-night cycle. Circadian timekeeping, which has been recognized in the 2017 Nobel Prize for Physiology or Medicine, offers a selective advantage to organisms by enabling them to anticipate and adapt to the day-night cycle. Disruption of this synchrony because of ever-increasing shift work, as well as widespread exposure to low levels of light at night, has been linked to diverse disorders such as cardiovascular disease and cancer.
The core mammalian circadian clock operates via a transcription-translation feedback loop generated through the concerted action of positive (CLOCK and BMAL1) and negative (PER2, CRY and REV-ERBa) transcriptional regulators. The importance of dynamics in this clock can be anticipated from the observation that ~ 50% of three out of the four core clock proteins are intrinsically disordered and lacking stable structure.
(B) Metamorphic proteins
The amino acid sequence of a protein generally codes for a unique tertiary and quaternary structure. This empirical rule has been shaken by the recent discovery of a class of proteins called metamorphic proteins, which can exist in more than one native state under slightly different conditions in the absence of ligands and cofactors. The two native states are generally in equilibrium with one another, interconvert rapidly between themselves, and also perform different biological functions. Metamorphic proteins emphasize the structural malleability of protein folds and provide a striking illustration for how a single static structure may not tell the whole story.
We are interested in understanding how the interconversion between the two native structures occurs both rapidly and efficiently so that the metamorphic system can function as a protein switch. Metamorphic proteins are also relevant from an evolutionary perspective, because they are considered as intermediates linking two native protein folds.
We are interested in understanding how the interconversion between the two native structures occurs both rapidly and efficiently so that the metamorphic system can function as a protein switch. Metamorphic proteins are also relevant from an evolutionary perspective, because they are considered as intermediates linking two native protein folds.
