Abstract:
: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.
journal_name
Nat Chem Bioljournal_title
Nature chemical biologyauthors
Dong C,Zhang H,Li L,Tempel W,Loppnau P,Min Jdoi
10.1038/s41589-018-0036-1subject
Has Abstractpub_date
2018-05-01 00:00:00pages
466-473issue
5eissn
1552-4450issn
1552-4469pii
10.1038/s41589-018-0036-1journal_volume
14pub_type
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