9PLR
CryoEM reconstruction of HUWE1-USP7 complex in the closed state
This is a non-PDB format compatible entry.
Summary for 9PLR
| Entry DOI | 10.2210/pdb9plr/pdb |
| EMDB information | 71721 |
| Descriptor | E3 ubiquitin-protein ligase HUWE1, Ubiquitin carboxyl-terminal hydrolase 7 (2 entities in total) |
| Functional Keywords | complex, e3-ligase-dub, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 610897.17 |
| 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 Cited by 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: 42753704DOI: 10.1016/j.molcel.2026.08.016 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.88 Å) |
Structure validation
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