6WZZ

GID4 in complex with VGLWKS peptide

Summary for 6WZZ

• Entry DOI: 10.2210/pdb6wzz/pdb
• Descriptor: Glucose-induced degradation protein 4 homolog, VGLWKS peptide, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: gid4, structural genomics, structural genomics consortium, sgc, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 20294.60

Authors

Dong, C.,Tempel, W.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2020-05-14, release date: 2020-06-17, Last modification date: 2023-10-18)

Primary citation

Dong, C.,Chen, S.J.,Melnykov, A.,Weirich, S.,Sun, K.,Jeltsch, A.,Varshavsky, A.,Min, J.
Recognition of nonproline N-terminal residues by the Pro/N-degron pathway.
Proc.Natl.Acad.Sci.USA, 117:14158-14167, 2020

PubMed Abstract: Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with a of 16 μM, whereas the otherwise identical Nt-Pro-bearing sequence PGLW binds to GID4 more tightly, with a of 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeast can target an Nt-IGLW-bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.

PubMed: 32513738
DOI: 10.1073/pnas.2007085117

Experimental method

X-RAY DIFFRACTION (1.6 Å)