Gp78 E3 Ubiquitin Ligase: Essential Functions and Contributions in Proteostasis

Abstract

As per the requirement of metabolism and fitness, normal cellular functions are controlled by several proteins, and their interactive molecular and signaling events at multiple levels. Protein quality control (PQC) mechanisms ensure the correct folding and proper utilization of these proteins to avoid their misfolding and aggregation. To maintain the optimum environment of complex proteome PQC system employs various E3 ubiquitin ligases for the selective degradation of aberrant proteins. Glycoprotein 78 (Gp78) is an E3 ubiquitin ligase that prevents multifactorial deleterious accumulation of different misfolded proteins via endoplasmic reticulum-associated degradation (ERAD). However, the precise role of Gp78 under stress conditions to avoid bulk misfolded aggregation is unclear, which can act as a crucial resource to establish the dynamic nature of the proteome. Present article systematically explains the detailed molecular characterization of Gp78 and also addresses its various cellular physiological functions, which could be crucial to achieving protein homeostasis. Here, we comprehensively represent the current findings of Gp78, which shows its PQC roles in different physiological functions and diseases; and thereby propose novel opportunities to better understand the unsolved questions for therapeutic interventions linked with different protein misfolding disorders.

Gp78 involvement in cellular proliferation: Can act as a promising modulator for cell cycle regulatory proteins?

“…In the current finding, we have noticed that overexpression of Gp78 influences the endogenous levels of cell cycle regulatory proteins. Previous reports indicate that E3 ubiquitin ligase Gp78 targets various metastasis suppressor and neurodegenerative disease associated proteins for their degradation (Chen et al, ; Joshi, Upadhyay, Kumar, & Mishra, ). It has been observed that tunicamycin treatment induces p27 levels, which suppresses cell cycle progression in melanoma cells (Han, Jin, Mei, & Wu, ).…”

Structural basis of generic versus specific E2–RING E3 interactions in protein ubiquitination

“…Toward this end GP78 sequester UBE2G2 to the ER via a specialized helix distal to its RING core, termed the UBE2G2‐binding region (G2BR). G2BR binds to UBE2G2 at UBC backside, extending the canonical E2–E3 contact area and markedly increasing UBE2G2–GP78 interaction affinity …”

“…G2BR binds to UBE2G2 at UBC backside, extending the canonical E2-E3 contact area and markedly increasing UBE2G2-GP78 interaction affinity. 69 In this noncanonical E2-E3 interaction, R578 and Q579 on G2BR coordinates E31 and N30 on the UBE2G2 β1-β2 loop, while at the other end of G2BR, K600 coordinates E45/E50 on the UBE2G2 β2-β3 loop, clamping the G2BR helix on the UBC backside. Meanwhile, several hydrophobic residues project toward the UBC backside.…”

Induction via Functional Protein Stabilization of Hepatic Cytochromes P450 upon gp78/Autocrine Motility Factor Receptor (AMFR) Ubiquitin E3-ligase Genetic Ablation in Mice: Therapeutic and Toxicological Relevance

“…cytoplasmic Hsc70-cochaperone, functions with its cognate UbcH5a E2 and Hsc70/Hsp70 in substrate ubiquitination (Ballinger at al., 1999;Connell et al, 2001;Murata et al, 2001;Jiang et al, 2001). gp78/AMFR (autocrine motility factor receptor) is a polytopic, transmembrane cell surface protein (Nabi et al, 1990), as well as ER-integral protein with a cytoplasmic domain containing a RING-finger and other subdomains critical to its recruitment of its cognate E2 (UBC7 or Ube2G2) and catalytic E3-ligase-mediated ubiquitination role (Fang et al, 2001;Chen et al, 2012;Joshi et al, 2017).…”