6ccr

Publication Abstract from PubMed

The N-end rule pathway senses the N-terminal destabilizing residues of degradation substrates for the ubiquitin-proteasome system, whose integrity shields against various human syndromes including cancer and cardiovascular diseases. GID4, a subunit of the ubiquitin ligase GID complex, has been recently identified as the N-recognin of the new branch of the N-end rule pathway responsible for recognizing substrates bearing N-terminal proline residues (Pro/N-degrons). However, the molecular mechanism of GID4-mediated Pro/N-degron recognition remains largely unexplored. Here, we report the first crystal structures of human GID4 alone and in complex with various Pro/N-degrons. Our complex crystal structures, together with biophysical analyses, delineate the GID4-mediated Pro/N-degron recognition mechanism and substrate selection criteria for the Pro/N-end rule pathway. These mechanistic data on the Pro/N-recognin activity of GID4 will serve as a foundation to facilitate the identification of authentic physiological substrates as well as the development of inhibitors of therapeutic values for the Pro/N-end rule pathway.

Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway.,Dong C, Zhang H, Li L, Tempel W, Loppnau P, Min J Nat Chem Biol. 2018 May;14(5):466-473. doi: 10.1038/s41589-018-0036-1. Epub 2018 , Apr 9. PMID:29632410^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.