Aggregation Gatekeepers and proteostasis in mammalian cells

Protein aggregation is driven by short aggregation-prone regions (APRs). Evolutionary selection against aggregation has led to the enrichment of so-called aggregation gatekeeper (GK) residues at the flanks of these APRs. The GKs both reduce the local intrinsic aggregation propensity of the sequence and mediate interaction with molecular chaperones and other cellular quality control factors. However, our understanding of this second role is only rudimentary, particularly in mammalian cells. We believe that GKs provide a simple tool for protein quality control that effectively signals the aggregation propensity of a polypeptide segment in the unfolded state, before aggregation actually happens. The overall aim of the project described here is therefore to chart the cellular factors that modify the folding and aggregation of unfolded protein molecules containing an APR, in particular those that can differentiate between GK types. With this project, we aim to make a decisive contribution to determining how and how much GKs impact routing of protein substrates through the PQC.

Keywords:Protein Quality Control, Protein folding and aggregation, Aggregation Gatekeepers, Molecular chaperones

Disciplines:Transcription and translation, Molecular biophysics, Proteins, Single-cell data analysis