Exploring The "Misfolding Problem" by Systematic Discovery and Analysis of Functional-But-Degraded Proteins

Mol Biol Cell. 2023 Sep 20:mbcE23060248. doi: 10.1091/mbc.E23-06-0248. Online ahead of print.ABSTRACTIn both health and disease, the ubiquitin-proteasome system (UPS) degrades point mutants that retain partial function but have decreased stability compared to their wild-type counterparts. This class of UPS substrate includes routine translational errors and numerous human disease alleles, such as the most common cause of cystic fibrosis, ΔF508-CFTR. Yet, there is no systematic way to discover novel examples of these "minimally misfolded" substrates. To address that shortcoming, we designed a genetic screen to isolate functional-but-degraded point mutants, and we used the screen to study soluble, monomeric proteins with known structures. These simple parent proteins yielded diverse substrates, allowing us to investigate the structural features, cytotoxicity, and small-molecule regulation of minimal misfolding. Our screen can support numerous lines of inquiry, and it provides broad access to a class of poorly understood but biomedically critical quality-control substrates.PMID:37729018 | DOI:10.1091/mbc.E23-06-0248

Source: Mol Biol Cell - September 20, 2023 Category: Molecular Biology Authors: Matthew P Flagg Breanna Lam Darren K Lam Tiffany M Le Andy Kao Yousif I Slaiwa Randolph Y Hampton Source Type: research