DNAJB6 as a guardian of disordered proteins
DNAJB6 as a guardian of disordered proteins
Proteins are essential for life, yet they can become harmful when they clump into non functional assemblies. To avoid this, cells rely on an intricate protein quality control system that includes molecular chaperones to keep proteins functional. This system is robust but not infallible, and its failure is linked to several age associated diseases. In recent years, the highly flexible, disordered regions of proteins have gained much attention given their crucial roles in cellular organization. However, their dynamic nature, essential for multifaceted functions, also makes them prone to clumping if not properly monitored.
This PhD research of Maiara Kolbe Musskopf focused on one molecular chaperone, DNAJB6, which protects several disordered proteins such as those found in nuclear pore complexes (NPCs)—the gateways between the nucleus and cytoplasm. NPCs rely on the disordered FG Nups, which are particularly at risk of clumping before they reach the NPC. DNAJB6 prevents this via its own special disordered region, ensuring that the chaperone itself forms gel like assemblies stable enough to protect FG Nups but not so stable that they become harmful. To fulfil its protective role during NPC assembly, DNAJB6 collaborates with the so far enigmatic protein MLF2. Additionally, preliminary data on a rare DNAJB6 variant revealed enhanced anti aggregation activity, likely via better exposure of its disordered region. Even beyond NPCs, DNAJB6 appears to act as a general guardian of disordered proteins throughout the cell.
The mechanistic insights from this work broaden our understanding of how cells prevent the clumping of disordered proteins and open avenues for rationally improving chaperone function.