Conserved disordered regions and ubiquitin-binding motifs within HUWE1 contribute to substrate targeting plasticity
Abstract
E3 ligases confer substrate specificity within ubiquitin-dependent pathways. However, the pleiotropic HECT-type E3 ligase HUWE1 targets a biochemically and structurally diverse set of substrates through mechanisms that remain largely unknown. We develop a combinatorial cell-based system integrating global proteomics, proximity labeling, and reporter assays to systematically interrogate HUWE1 sequence features that enable substrate targeting. We define a robust HUWE1 activity signature consisting of putative substrates that accumulate upon HUWE1 impairment across multiple cell lines. By re-expressing a panel of HUWE1 deletion mutants, we find that both the largest intrinsically disordered region and the conserved ubiquitin-binding motifs contribute to substrate targeting. Structural modeling and domain analysis further suggest that HUWE1 achieves targeting plasticity through multivalent interactions, engaging both disordered and structured regions within its substrates. Together, our findings establish a framework for understanding how large, modular E3 ligases exploit intrinsic disorder and multivalency to shape their substrate repertoires.
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BibTeX
@article{ge2026conserved,
title = {{Conserved disordered regions and ubiquitin-binding motifs within HUWE1 contribute to substrate targeting plasticity}},
author = {Xuezhen Ge and Fulin Jiang and Caesar A. De La Fuente and Trivikram Rajkhowa and Chumo Chen and Rathipriya Viswanathan and Aida Husain and Eric J. Bennett},
journal = {Cell Reports},
year = {2026},
month = oct,
doi = {10.1016/j.celrep.2026.118219},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726012982},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Conserved disordered regions and ubiquitin-binding motifs within HUWE1 contribute to substrate targeting plasticity
AU - Xuezhen Ge
AU - Fulin Jiang
AU - Caesar A. De La Fuente
AU - Trivikram Rajkhowa
AU - Chumo Chen
AU - Rathipriya Viswanathan
AU - Aida Husain
AU - Eric J. Bennett
PY - 2026
DA - 2026/10/31
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118219
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726012982
AB - E3 ligases confer substrate specificity within ubiquitin-dependent pathways. However, the pleiotropic HECT-type E3 ligase HUWE1 targets a biochemically and structurally diverse set of substrates through mechanisms that remain largely unknown. We develop a combinatorial cell-based system integrating global proteomics, proximity labeling, and reporter assays to systematically interrogate HUWE1 sequence features that enable substrate targeting. We define a robust HUWE1 activity signature consisting of putative substrates that accumulate upon HUWE1 impairment across multiple cell lines. By re-expressing a panel of HUWE1 deletion mutants, we find that both the largest intrinsically disordered region and the conserved ubiquitin-binding motifs contribute to substrate targeting. Structural modeling and domain analysis further suggest that HUWE1 achieves targeting plasticity through multivalent interactions, engaging both disordered and structured regions within its substrates. Together, our findings establish a framework for understanding how large, modular E3 ligases exploit intrinsic disorder and multivalency to shape their substrate repertoires.
SN - 2211-1247
ER -