7MOP

Cryo-EM structure of human HUWE1 in complex with DDIT4

Summary for 7MOP

• Entry DOI: 10.2210/pdb7mop/pdb
• Related: 7JQ9
• EMDB information: 22427 22428 22429 22430 22431 23925
• Descriptor: E3 ubiquitin-protein ligase HUWE1, DNA damage-inducible transcript 4 protein (2 entities in total)
• Functional Keywords: ubiquitin, quality control, e3 ligase, protein degradation, transferase, transferase-apoptosis complex, transferase/apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 514846.35

Authors

Hunkeler, M.,Fischer, E.S. (deposition date: 2021-05-03, release date: 2021-07-28, Last modification date: 2024-11-13)

Primary citation

Hunkeler, M.,Jin, C.Y.,Ma, M.W.,Monda, J.K.,Overwijn, D.,Bennett, E.J.,Fischer, E.S.
Solenoid architecture of HUWE1 contributes to ligase activity and substrate recognition.
Mol.Cell, 81:3468-, 2021

PubMed Abstract: HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal ∼3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization.

PubMed: 34314700
DOI: 10.1016/j.molcel.2021.06.032

Experimental method

ELECTRON MICROSCOPY (3.3 Å)