Resumen de Connexió entre desorde proteic, plegament i agregació: implicacions fisiològiques i patològiques
Intrinsically Disordered Proteins (IDPs) and Regions (IDRs) are a class of polypeptides that lack defined three-dimensional structures. Instead, they populate a dynamic ensemble of flexible conformers that endorse them with unique properties to interact with multiple partners and mediate in signal transduction. Environmental factors, post-translational modifications, and binding partners impact the IDPs' conformational space, promoting structural transitions that regulate their functions.
This thesis has addressed the disorder-to-order transition phenomenon from two perspectives: its physiological function and its implication in disease.
First, we studied the redox-driven conformational transition of two small disulfide-rich mitochondrial proteins. We demonstrate that both polypeptides follow different folding pathways despite sharing a common fold. The reaction is determined by the primary sequence of amino acids and the reduced and unfolded species' conformational state. Reduced COX17 is mostly disordered, and its folding is directed by the local packing of a loop region. In contrast, TRIAP1 reduced state resembles a molten globule. This early loosely packed conformer biases and slows down the folding pathway, but its population is unavoidable, because it arises from functional constraints in the folded state.
Second, we addressed the sequential overlap between amyloidogenic and interaction regions in the context of disordered proteins, to demonstrate that the extended C-terminus of the proteostasis guardian protein, Hsf1, contains a cryptic prion-like domain with the potential to assemble into amyloid fibrils.
Finally, we focused our attention on the aggregation of -synuclein, the main culprit of the onset and progression of Parkinson's Disease. This protein's disordered nature precludes the use of rational strategies to design effective drugs that block its transition to ordered and deleterious amyloids. Therefore we implemented a blind high-throughput screening methodology to identify novel small molecules that might succeed in that purpose. This effort rendered three promising candidates: Syunclean-D, ZPD-2, and ZPDm. Their anti-amyloidogenic and neuroprotective properties were characterized, and their pharmacologic potential was discussed.
