Guardians of protein disorder
Description: Surprisingly, control of disorder of proteins plays a crucial role in the physiology of cells. Proteins with intrinsically disordered domains have the capacity to phase separate, resulting in membraneless compartments containing high concentrations of proteins in a liquid- or gel-like state. The nuclear pore complex, the conserved gate to a cell’s nucleus, is the best-studied example of a structure that relies on phase separated, intrinsically disordered proteins (IDPs) for its essential function. IDPs are also prone to aggregation, and amyloid formation of IDPs is often associated with pathology, as observed in neurodegenerative diseases.
We know virtually nothing about the mechanisms that ensure that IDPs exist in the proper phase state, but two groups of proteins appear critical—chaperones, preventing aggregation of disease related IDPs, and nuclear transport receptors, whose classical function is to shuttle cargo through the nuclear pore complex. Intriguingly, recent studies show that chaperones impact nuclear transport and, vice versa, that nuclear transport receptors act on disease related IDPs.
The central question that we will answer is how nuclear transport receptors and chaperones impact the phase transitions of IDPs in guarding the proteome against aggregation, ensuring proper NPC function, and avoiding pathogenesis. We will address this challenge with a cross-disciplinary consortium of leading experts from the fields of nuclear transport and chaperone-regulated protein quality control. By combining in silico, in vitro and cell biological approaches, we aim to discover the mechanisms that guard IDPs from aggregating, and gain an in-depth understanding of the fundamental principles that control the phase transitions of IDPs. By uncovering how IDPs transform from functionally important in normal physiology to drivers of pathology, our work will create opportunities for the development of treatments targeting diverse aggregation pathologies.
Funding type: grant
Funder scheme: Open Competitie ENW XL (voorheen OC ENW-GROOT) Ronde 2019
Start date: 2020-11-01
Investigator: Liesbeth Veenhoff
Institution: Universitair Medisch Centrum Groningen
Funded outputs count: 28
Funder award ID: OCENW.GROOT.2019.068
OpenAlex ID: G4653753151