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TitleSolenoid architecture of HUWE1 contributes to ligase activity and substrate recognition.
Journal, issue, pagesMol Cell, Vol. 81, Issue 17, Page 3468-33480.e7, Year 2021
Publish dateSep 2, 2021
AuthorsMoritz Hunkeler / Cyrus Y Jin / Michelle W Ma / Julie K Monda / Daan Overwijn / Eric J Bennett / Eric S Fischer /
PubMed AbstractHECT 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 ...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.
External linksMol Cell / PubMed:34314700 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 4.5 Å
Structure data

EMDB-22427, PDB-7jq9:
Cryo-EM structure of human HUWE1
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-22428: Cryo-EM structure of human HUWE1 (focused on HECT)
PDB-7mwd: HUWE1 in map with focus on HECT
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-22429: Cryo-EM structure of human HUWE1 (focused on WWE)
PDB-7mwe: HUWE1 in map with focus on WWE
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-22430: Cryo-EM structure of human HUWE1 (focused on interface)
PDB-7mwf: HUWE1 in map with focus on interface
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-22431:
Cryo-EM structure of human HUWE1 (non-crosslinked)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-23925, PDB-7mop:
Cryo-EM structure of human HUWE1 in complex with DDIT4
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-23931:
Cryo-EM structure of human HUWE1 (d169-189 variant)
Method: EM (single particle) / Resolution: 4.5 Å

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Ubiquitin / Quality Control / E3 ligase / protein degradation / TRANSFERASE/Apoptosis / TRANSFERASE-Apoptosis complex

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