6QCG

PCNA complex with Cdt1 N-terminal PIP-box peptide

6QCG の概要

• エントリーDOI: 10.2210/pdb6qcg/pdb
• 分子名称: Proliferating cell nuclear antigen, DNA replication factor Cdt1 (3 entities in total)
• 機能のキーワード: dna replication, ubiquitination, clr4, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 184938.49

構造登録者

Perrakis, A.,von Castelmur, E. (登録日: 2018-12-28, 公開日: 2019-01-23, 最終更新日: 2024-11-06)

主引用文献

Hayashi, A.,Giakoumakis, N.N.,Heidebrecht, T.,Ishii, T.,Panagopoulos, A.,Caillat, C.,Takahara, M.,Hibbert, R.G.,Suenaga, N.,Stadnik-Spiewak, M.,Takahashi, T.,Shiomi, Y.,Taraviras, S.,von Castelmur, E.,Lygerou, Z.,Perrakis, A.,Nishitani, H.
Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2E3 ligase activity to Cdt1.
Life Sci Alliance, 1:e201800238-e201800238, 2018

PubMed Abstract: The CRL4 ubiquitin ligase complex is an essential regulator of cell-cycle progression and genome stability, ubiquitinating substrates such as p21, Set8, and Cdt1, via a display of substrate degrons on proliferating cell nuclear antigens (PCNAs). Here, we examine the hierarchy of the ligase and substrate recruitment kinetics onto PCNA at sites of DNA replication. We demonstrate that the C-terminal end of Cdt2 bears a PCNA interaction protein motif (PIP box, Cdt2), which is necessary and sufficient for the binding of Cdt2 to PCNA. Cdt2 binds PCNA directly with high affinity, two orders of magnitude tighter than the PIP box of Cdt1. X-ray crystallographic structures of PCNA bound to Cdt2 and Cdt1 show that the peptides occupy all three binding sites of the trimeric PCNA ring. Mutating Cdt2 weakens the interaction with PCNA, rendering CRL4 less effective in Cdt1 ubiquitination and leading to defects in Cdt1 degradation. The molecular mechanism we present suggests a new paradigm for bringing substrates to the CRL4-type ligase, where the substrate receptor and substrates bind to a common multivalent docking platform to enable subsequent ubiquitination.

PubMed: 30623174
DOI: 10.26508/lsa.201800238

実験手法

X-RAY DIFFRACTION (3.4 Å)