Getting in Shape: Targeting the Etiology of Protein Misfolding Diseases – Celebrating Jeffery Kelly's Pioneering Work
Year: 2024
Type: article
Abstract: We are excited to share this special issue dedicated to Jeffery Kelly, commemorating his 2023 Wolf Prize in Chemistry.This award recognizes his pioneering research accomplishments, which have dramatically changed our fundamental understanding of how proteins (mis)fold in vitro and in vivo while at the same time leveraging those discoveries to change the lives of patients across the globe.The award specifically refers to the latter: "for developing a clinical strategy to ameliorate pathological protein aggregation".This is exemplified by the development of Tafamidis, [1] the first clinically approved molecule to treat a disease of protein misfolding.[2,3] Jeff's discovery that protein misfolding of transthyretin (TTR) is an obligate step prior to protein aggregation [4] established that preventing the accumulation of misfolded proteins can block disease pathology.Rigorous biochemical and biophysical characterization established that transthyretin tetramer dissociation into monomers is the rate-limiting step that initiates protein misfolding.[5] This critical insight motivated the development of small molecules that could stabilize the native conformation of TTR, [6] culminating in the development and clinical approval of Tafamidis.Later, Jeff and his collaborators introduced the idea of protein homeostasis (or proteostasis).[7] Protein folding and maturation into its native structure is not only governed by the intrinsic stability of each polypeptide chain, but in a cellular environment, the large ensemble of molecular chaperones, cochaperones, other protein quality factors, and their interacting
Source: Israel Journal of Chemistry
Authors: Lars Plate, Joseph C. Genereux
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4407040878