2. Academic Validation
  3. Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase

Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase

  • Mol Cell. 2018 Dec 6;72(5):813-822.e4. doi: 10.1016/j.molcel.2018.10.021.
Domniţa-Valeria Rusnac 1,  Hsiu-Chuan Lin 2,  Daniele Canzani 3,  Karena X Tien 1,  Thomas R Hinds 1,  Ashley F Tsue 1,  Matthew F Bush 3,  Hsueh-Chi S Yen 2,  Ning Zheng 4
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • 2 Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei 10617, Taiwan.
  • 3 Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • 4 Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
PMID: 30526872 DOI: 10.1016/j.molcel.2018.10.021
Abstract

Aberrant proteins can be deleterious to cells and are cleared by the ubiquitin-proteasome system. A group of C-end degrons that are recognized by specific cullin-RING ubiquitin E3 Ligases (CRLs) has recently been identified in some of these abnormal polypeptides. Here, we report three crystal structures of a CRL2 substrate receptor, KLHDC2, in complex with the diglycine-ending C-end degrons of two early-terminated selenoproteins and the N-terminal proteolytic fragment of USP1. The E3 recognizes the degron Peptides in a similarly coiled conformation and cradles their C-terminal diglycine with a deep surface pocket. By hydrogen bonding with multiple backbone carbonyls of the Peptides, KLHDC2 further locks in the otherwise degenerate degrons with a compact interface and unexpected high affinities. Our results reveal the structural mechanism by which KLHDC2 recognizes the simplest C-end degron and suggest a functional necessity of the E3 to tightly maintain the low abundance of its select substrates.

Keywords

C-end degron; DesCEND; E3; KLHDC2; USP1; crystal structure; cullin; protein degradation; selenoproteins; ubiquitin.

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