Increasing functional versatility of proteins by regulated unfolding and exposing disordered regions
Proteins are the fundamental executor molecules of living cells. They are polymers of amino acids and their functioning is tightly linked with their structure, i.e. the precise positioning of atoms. Recently, it has been shown that proteins may remain unstructured/disordered and yet be functional. More excitingly, certain proteins can interconvert between different folded structures and undergo a change between folded and unstructured conformations in a controlled and reversible manner (Regulated Unfolding; RU). In certain cases whole protein domains unfold as a result of minor chemical modifications, so called post-translational modifications (PTMs), exposing cryptic disordered segments affecting both protein cellular localization and interactions. Thus a fundamental open question is how prevalent is regulated unfolding and what are the underlying molecular principles?
We hypothesize that RU is widely prevalent, because by conditionally exposing disordered regions hosting short linear interaction motifs (SLiMs) reversible conformational changes could alter the cellular localization and interactions of proteins and provide increased functional plasticity during conditions such as stress. The reason why RU remained understudied so far is most probably the lack of structural information for modified proteins.
We develop and apply an inter-disciplinary computational and experimental approach involving the targeted discovery and characterization of proteins undergoing RU to elucidate the prevalence and biological relevance. Introducing regulated unfolding as a novel layer of protein function regulation will lay the foundations of a novel concept in biology.