How kelch domain-containing protein 3 distinguishes between the C-end degron of herpesviral protein UL49.5 and its mutants – Insights from molecular dynamics

• Published in: Bioorganic & medicinal chemistry Vol. 109; p. 117795
• Main Author: Ślusarz, Magdalena J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-07-2024
• Subjects: Degron recognition; E3 ubiquitin ligase; Herpesvirus; KLHDC3; UL49.5; UL49.5; KLHDC3; E3 ubiquitin ligase; Degron recognition; Herpesvirus
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117795

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The C-terminal residues of proteins can function as degrons recognized by ubiquitin ligases for proteasomal degradation. Kelch domain-containing protein 3 (KLHDC3) is a substrate receptor for E3 ubiquitin ligase (Cullin2-RING ligase) that targets the C-terminal degrons. UL49.5 is 96 amino-acid type 1 transmembrane protein from bovine herpesvirus 1. Herpesviruses have evolved highly effective strategies to evade the antiviral immune response. One of these strategies is inhibition of the antigen processing and presentation pathway by MHC I, thereby reducing the presentation of the antigenic peptides on the surface of the infected cell. Recently, it has been demonstrated that UL49.5 triggers TAP degradation via recruiting the E3 ubiquitin ligase to TAP. Moreover, the mutagenesis revealed that the mutations within the UL49.5 C-degron sequence (93RGRG96) affect binding of UL49.5 to KLHDC3.
In this work the molecular dynamics of KLHDC3 in complexes with the C-terminal decapeptide of the herpesviral protein UL4.95 and its three mutants has been employed to provide a framework for understanding molecular recognition of UL49.5 by KLHDC3. The findings of this study give insights into the interactions of the various degrons with KLHDC3. During the molecular dynamics, an active RGKG mutant adopts a conformation similar to that of the wild type decapeptide, whereas the conformations of two inactive mutants, KGRG and RGRD are significantly different. Both R93K and G96D mutations impair the interactions of the C-terminal glycine with KLHDC3.
The findings of this study expand the existing knowledge about the mechanism of protein recognition by Cullin2-RING ligases thus contributing to the design of antiviral and anticancer drugs that can selectively promote or inhibit degradation of the proteins of interest.