9PLQ

HUWE1(CS)-Ubiquitin bound to the HECT domain

Summary for 9PLQ

• Entry DOI: 10.2210/pdb9plq/pdb
• EMDB information: 71720
• Descriptor: E3 ubiquitin-protein ligase HUWE1, Ubiquitin (2 entities in total)
• Functional Keywords: ubiquitin complex, huwe1, e3 ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 490985.11

Authors

Yatskevich, S.,Juszkiewicz, S. (deposition date: 2025-07-16, release date: 2026-07-22, Last modification date: 2026-09-30)

Primary citation

Yatskevich, S.,Mohapatra, J.,Mroue, R.,Phu, L.,Leitner, A.,Azumaya, C.M.,Vandlen, R.,Cheung, T.K.,Soong, T.H.,Rose, C.M.,Ori, A.,Ciferri, C.,Juszkiewicz, S.
Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.
Mol.Cell, 86:3803-3821.e17, 2026

PubMed Abstract: Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1's ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7's catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.

PubMed: 42753704
DOI: 10.1016/j.molcel.2026.08.016

Experimental method

ELECTRON MICROSCOPY (3.19 Å)