9IVD

Cryo-EM structure of CyclinD1 bound AMBRA1-DDB1

Summary for 9IVD

• Entry DOI: 10.2210/pdb9ivd/pdb
• EMDB information: 60925
• Descriptor: G1/S-specific cyclin-D1, Activating molecule in BECN1-regulated autophagy protein 1, DNA damage-binding protein 1 (3 entities in total)
• Functional Keywords: e3 ligase, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 205441.43

Authors

Wang, Y.,Liu, M.,Su, M.-Y.,Stjepanovic, G. (deposition date: 2024-07-23, release date: 2025-04-23, Last modification date: 2025-07-16)

Primary citation

Wang, Y.,Liu, M.,Wang, S.,Mai, X.,Wang, X.,Teng, F.,Lyu, T.,Su, M.Y.,Stjepanovic, G.
Mechanism of D-type cyclin recognition by the AMBRA1 E3 ligase receptor.
Sci Adv, 11:eadu8708-eadu8708, 2025

PubMed Abstract: AMBRA1 is a tumor 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 3.55-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 Thr residue in the C-terminal phosphodegron site of D-type cyclins. The phosphodegron motif folds into a turn-like conformation, followed by a 3 helix that promotes its assembly with AMBRA1. In addition, 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 cyclin structure enhances the knowledge of the molecular mechanisms that govern the cell cycle control and may lead to potential therapeutic approaches for cancers linked to abnormal cyclin D activity.

PubMed: 40408472
DOI: 10.1126/sciadv.adu8708

Experimental method

ELECTRON MICROSCOPY (3.55 Å)