Gid4, Glucose-Induced Degradation 4, is a substrate receptor subunit of the C-terminal to LisH (CTLH) ubiquitin ligase complex. It recognizes substrates with Pro/N-degrons, playing a role in the ubiquitin-proteasome system and the Pro/N-end rule pathway, which is crucial for maintaining protein homeostasis [1,4,5,8]. Gid4 is involved in regulating multiple cellular processes such as cell cycle progression, metabolism, and cell migration [2].

In terms of core findings, PFI-7, a chemical probe, was used to identify GID4 interactors and GID4-regulated proteins. GID4 interactors are enriched for nucleolar proteins like DDX21 and DDX50, and proteins like HMGCS1 have their cellular levels regulated by GID4 [1]. The hGID/GID4 E3 ligase binds and ubiquitinates ARHGAP11A, targeting it for proteasomal degradation, and GID4 inactivation impairs cell motility [2]. Small molecule binders of GID4 have been discovered, positioning GID4-CTLH as an E3 for targeted protein degradation (TPD) [3]. The molecular mechanism of GID4-mediated Pro/N-degron recognition has been explored through crystal structures and biophysical analyses [4]. In silico studies have investigated the binding of Gid4 to gluconeogenic enzymes like Pck1, Icl1, Fbp1, and Mdh2 [5,8]. Gid4 has been engineered to create a better N-terminal proline binder [6]. In yeast, Gid4 is tightly regulated to adjust gluconeogenesis [7]. Novel chemical tools for GID4 have been developed [9]. Alterations in GID4 are associated with higher telomeric content in soft tissue sarcoma (not otherwise specified) [10].

In conclusion, Gid4 is essential for recognizing Pro/N-degron-containing substrates and is involved in multiple cellular processes. Its study through chemical probes, in silico methods, and genetic engineering has provided insights into its function in protein degradation, cell migration, and disease-associated processes such as telomere elongation in sarcomas. These findings contribute to understanding the biological functions related to protein homeostasis and disease mechanisms.

References:

1. Owens, Dominic D G, Maitland, Matthew E R, Khalili Yazdi, Aliakbar, Schild-Poulter, Caroline, Arrowsmith, Cheryl H. 2024. A chemical probe to modulate human GID4 Pro/N-degron interactions. In Nature chemical biology, 20, 1164-1175. doi:10.1038/s41589-024-01618-0. https://pubmed.ncbi.nlm.nih.gov/38773330/

2. Bagci, Halil, Winkler, Martin, Grädel, Benjamin, Pertz, Olivier, Peter, Matthias. 2024. The hGIDGID4 E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration. In Life science alliance, 7, . doi:10.26508/lsa.202403046. https://pubmed.ncbi.nlm.nih.gov/39389782/

3. Chana, Chetan K, Maisonneuve, Pierre, Posternak, Ganna, Gingras, Anne-Claude, Sicheri, Frank. 2022. Discovery and Structural Characterization of Small Molecule Binders of the Human CTLH E3 Ligase Subunit GID4. In Journal of medicinal chemistry, 65, 12725-12746. doi:10.1021/acs.jmedchem.2c00509. https://pubmed.ncbi.nlm.nih.gov/36117290/

4. Dong, Cheng, Zhang, Heng, Li, Li, Loppnau, Peter, Min, Jinrong. 2018. Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway. In Nature chemical biology, 14, 466-473. doi:10.1038/s41589-018-0036-1. https://pubmed.ncbi.nlm.nih.gov/29632410/

5. Ismail, Alaa M, Elfiky, Abdo A, Elshemey, Wael M. 2019. Recognition of the gluconeogenic enzyme, Pck1, via the Gid4 E3 ligase: An in silico perspective. In Journal of molecular recognition : JMR, 33, e2821. doi:10.1002/jmr.2821. https://pubmed.ncbi.nlm.nih.gov/31883179/

6. Ikonomova, Svetlana P, Yan, Bo, Sun, Zhiyi, Marino, John P, Kelman, Zvi. 2024. Engineering GID4 for use as an N-terminal proline binder via directed evolution. In Biotechnology and bioengineering, 122, 179-188. doi:10.1002/bit.28868. https://pubmed.ncbi.nlm.nih.gov/39450770/

7. Menssen, Ruth, Bui, Kim, Wolf, Dieter H. 2018. Regulation of the Gid ubiquitin ligase recognition subunit Gid4. In FEBS letters, 592, 3286-3294. doi:10.1002/1873-3468.13229. https://pubmed.ncbi.nlm.nih.gov/30136317/

8. Elfiky, Abdo A, Ismail, Alaa M, Elshemey, Wael M. 2019. Recognition of gluconeogenic enzymes; Icl1, Fbp1, and Mdh2 by Gid4 ligase: A molecular docking study. In Journal of molecular recognition : JMR, 33, e2831. doi:10.1002/jmr.2831. https://pubmed.ncbi.nlm.nih.gov/31863529/

9. Yazdi, Aliakbar Khalili, Perveen, Sumera, Dong, Cheng, Vedadi, Masoud, Owen, Dafydd R. 2024. Chemical tools for the Gid4 subunit of the human E3 ligase C-terminal to LisH (CTLH) degradation complex. In RSC medicinal chemistry, 15, 1066-1071. doi:10.1039/d3md00633f. https://pubmed.ncbi.nlm.nih.gov/38516600/

10. Sharaf, Radwa, Jin, Dexter X, Grady, John, Thomas, David M, Montesion, Meagan. 2023. A pan-sarcoma landscape of telomeric content shows that alterations in RAD51B and GID4 are associated with higher telomeric content. In NPJ genomic medicine, 8, 26. doi:10.1038/s41525-023-00369-6. https://pubmed.ncbi.nlm.nih.gov/37709802/