RT Journal Article
SR Electronic
T1 Mechanism of D-type cyclins recognition by the AMBRA1 E3 ligase receptor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.12.17.628619
DO 10.1101/2024.12.17.628619
A1 Wang, Yang
A1 Liu, Ming
A1 Wang, Shan
A1 Mai, Xinyi
A1 Wang, Xi
A1 Teng, Fei
A1 Lyu, Tianrui
A1 Su, Ming-Yuan
A1 Stjepanovic, Goran
YR 2024
UL http://biorxiv.org/content/early/2024/12/18/2024.12.17.628619.abstract
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.