Regulatory functions of intrinsically disordered electronegative clusters (ENC) in RNA-binding proteins (Funded by NSF MCB)
Interaction between biomolecules is essential for life. While most proteins have stable three-dimensional structures, a significant number of proteins have been shown to lack a stable three-dimensional structure and are known as intrinsically disordered proteins. It has been shown that proteins that interact with RNA contain regions that are intrinsically disordered, which are essential for the protein-RNA binding. The investigators of this project have shown that most abundant disordered regions in RNA-binding proteins encode clusters of acidic residues or phosphorylation sites that give these regions an overall negative charge. Like tails that help animals to balance and to swish away insects, the disordered protein regions help proteins to balance surface charges for stability and swish away nonspecific ligands. This project will explore how these electronegative clusters modulate protein function. Studying these proteins will provide insights into key biological processes, such as transient folding of disordered proteins, site selection in ribosomal biogenesis, and alternative splicing.
The central roles of SRSF1 in early-stage spliceosome assembly (Funded by NIH NIGMS)
Alternative splicing processes over 95% of human mRNA and enables a single gene to encode distinct protein isoforms of different functions. Dysregulation of alternative splicing causes incorrect selection of exons and consequently various human diseases. Alternative exons are selected in early-stage spliceosome assembly. Due to our limited knowledge about early-stage spliceosome assembly, it is still challenging to develop therapies for diseases related to aberrant RNA splicing. Early-stage spliceosome assembly involves selection of exons and recruitment to the splicing sites of ribonucleoprotein complexes U1 and U2. These processes depend on the interplay of Ser/Arg-rich proteins (SR), U1-70K and U2AF-35. SR proteins are the key factors that coordinate all these events. The SR family consists of 12 members and shares Arg-Ser repetitive regions (RS) that are subjected to phosphorylation. In this proposal, we have selected the prototype of the family, SRSF1, as a model to investigate the central roles of SR proteins in spliceosome assembly.