Lysine deserts and cullin-RING ligase receptors: Navigating untrodden paths in proteostasis

Natalia A Szulc; Małgorzata Piechota; Lilla Biriczová; Pankaj Thapa; Wojciech Pokrzywa

doi:10.1016/j.isci.2023.108344

Lysine deserts and cullin-RING ligase receptors: Navigating untrodden paths in proteostasis

iScience. 2023 Oct 28;26(11):108344. doi: 10.1016/j.isci.2023.108344. eCollection 2023 Nov 17.

Authors

Natalia A Szulc¹, Małgorzata Piechota¹, Lilla Biriczová¹, Pankaj Thapa¹, Wojciech Pokrzywa¹

Affiliation

¹ Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, 4 Ks. Trojdena Str., 02-109 Warsaw, Poland.

Abstract

The ubiquitin-proteasome system (UPS) governs the degradation of proteins by ubiquitinating their lysine residues. Our study focuses on lysine deserts - regions in proteins conspicuously low in lysine residues - in averting ubiquitin-dependent proteolysis. We spotlight the prevalence of lysine deserts among bacteria leveraging the pupylation-dependent proteasomal degradation, and in the UPS of eukaryotes. To further scrutinize this phenomenon, we focused on human receptors VHL and SOCS1 to ascertain if lysine deserts could limit their ubiquitination within the cullin-RING ligase (CRL) complex. Our data indicate that the wild-type and lysine-free variants of VHL and SOCS1 maintain consistent turnover rates, unaltered by CRL-mediated ubiquitination, hinting at a protective mechanism facilitated by lysine deserts. Nonetheless, we noted their ubiquitination at non-lysine sites, alluding to alternative regulation by the UPS. Our research underscores the role of lysine deserts in limiting CRL-mediated ubiquitin tagging while promoting non-lysine ubiquitination, thereby advancing our understanding of proteostasis.

Keywords: Enzymology; Evolutionary biology; Molecular interaction; Properties of biomolecules; Protein.