Shedding light on the flexible regions of a key human protein, SFPQ
What is it about?
SFPQ is a critical protein found in human cells that helps regulate gene activity. It belongs to a protein family called the DBHS family and often works together with a close family member, NONO. These proteins are involved in many essential cellular processes, and changes in how they behave have been linked to neurological diseases and cancer. SFPQ contains both structured regions—which form stable, folded shapes—and unstructured regions, known as intrinsically disordered regions (IDRs). These IDRs don’t settle into a single shape; they are more like very flexible, dynamic spaghetti regions, but they play important roles in how the protein interacts with other molecules and how it forms dynamic assemblies inside cells. Unfortunately, because of their flexibility, IDRs are difficult to study using traditional structural techniques. In this study, we used small-angle X-ray and neutron scattering (SAXS and SANS), along with cross-linking mass spectrometry (XL-MS), to investigate the flexible regions of SFPQ. We found that the regions at both ends of the protein are long, disordered (think protein spaghettii), and able to move freely in solution. Our modelling suggests these ends can come close enough to interact with each other or with the central folded region. We also found that full-length SFPQ can exchange dimer partners, meaning it may dynamically mix with other SFPQ molecules in the cell. These findings provide new insight into the architecture and behaviour of SFPQ, and offer clues into how its flexible parts contribute to its many roles in health and disease.
Why is it important?
SFPQ is a critical protein for human health, involved in essential cellular processes and linked to neurological diseases and some cancers. Understanding SFPQ is not only medically relevant, but also biologically important, as the protein is conserved across all mammals. This study also highlights a multi-pronged experimental strategy for investigating complex proteins that are often difficult to analyse using traditional methods, offering a valuable roadmap for studying other challenging systems.