Informace o projektu
Manipulating Proteoforms with Chemical Tools (Mgr. Tomáš Fiala, Ph.D.)

The human body can synthesize ~70’000 different proteins. These proteins diversify into millions of proteoforms, mainly by acquiring additional functionalities called post-translational modifications (PTMs). Distinct proteoforms are often found in different cell types and have diverse functions. Dysregulation of specific proteoforms is associated with many diseases, including neurodegeneration or cancers, highlighting the need for their study and modulation. Nature has evolved enzymes to switch between individual protein forms by installing and removing PTMs. However, for many PTMs, the responsible enzymes are either not known, non-existent, or highly promiscuous. Such PTMs cannot be studied by common biological methods that target these enzymes. PROTEOFORMER addresses these needs with chemical tools: tailored reagents that (i) recognize the protein target, (ii) bring a reactive group to the target’s surface, and (iii) install or remove a PTM via a proximity-induced reaction. Specifically, it focuses on sulfotyrosine, a difficult-to-study PTM primarily found on extracellular proteins. To manipulate sulfotyrosine residues, PROTEOFORMER will (1) develop new chemical reagents capable of introducing or removing sulfate to/from tyrosine, (2) test and optimize the reagents’ proximity-induced reactivity with a bespoke supramolecular platform based on peptide nucleic acids, and (3) apply the optimized reagents in probe development for sulfotyrosine manipulation in proteins. The probes will allow for dissecting the influence of sulfotyrosine PTMs on signaling related to chronic brain inflammation and Alzheimer’s disease. Overall, PROTEOFORMER develops new chemistry for manipulating proteoforms beyond current capabilities. This general concept represents a chemical solution to a long-standing challenge in biology intractable with traditional methods.