PT  - JOURNAL ARTICLE
AU  - Wang, Yang
AU  - Liu, Ming
AU  - Wang, Shan
AU  - Mai, Xinyi
AU  - Wang, Xi
AU  - Teng, Fei
AU  - Lyu, Tianrui
AU  - Su, Ming-Yuan
AU  - Stjepanovic, Goran
TI  - Mechanism of D-type cyclins recognition by the AMBRA1 E3 ligase receptor
AID  - 10.1101/2024.12.17.628619
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.12.17.628619
4099  - http://biorxiv.org/content/early/2024/12/18/2024.12.17.628619.short
4100  - http://biorxiv.org/content/early/2024/12/18/2024.12.17.628619.full
AB  - AMBRA1 is a tumour suppressor protein that functions as a substrate receptor in the ubiquitin conjugation system and regulates the stability of D-type cyclins and cell proliferation. Here, we present the cryo-EM structure of cyclin D1 bound AMBRA1-DDB1 complex at 3.5 Å resolution. The structure reveals a substrate interaction surface on the AMBRA1 WD40 domain that specifically binds to the C-terminal region of D-type cyclins. This interaction is dependent on the phosphorylation of Thr286 residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation followed by a 310 helix that promotes its assembly with AMBRA1. Additionally, we show that AMBRA1 mutants, which are defective in cyclin D1 binding, lead to cyclin D1 accumulation and DNA damage. Understanding the AMBRA1-D-type cyclins structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to new therapeutic approaches for cancers linked to abnormal cyclin D activity.Competing Interest StatementThe authors have declared no competing interest.