Abstract
The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 345-357.e6 |
| Journal | Molecular Cell |
| Volume | 66 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 4 2017 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
A Tunable Brake for HECT Ubiquitin Ligases. / Chen, Zan; Jiang, Hanjie; Xu, Wei; Li, Xiaoguang; Dempsey, Daniel R.; Zhang, Xiangbin; Devreotes, Peter; Wolberger, Cynthia; Amzel, L. Mario; Gabelli, Sandra B.; Cole, Philip A.
In: Molecular Cell, Vol. 66, No. 3, 04.05.2017, p. 345-357.e6.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Tunable Brake for HECT Ubiquitin Ligases
AU - Chen,Zan
AU - Jiang,Hanjie
AU - Xu,Wei
AU - Li,Xiaoguang
AU - Dempsey,Daniel R.
AU - Zhang,Xiangbin
AU - Devreotes,Peter
AU - Wolberger,Cynthia
AU - Amzel,L. Mario
AU - Gabelli,Sandra B.
AU - Cole,Philip A.
PY - 2017/5/4
Y1 - 2017/5/4
N2 - The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.
AB - The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.
UR - http://www.scopus.com/inward/record.url?scp=85018767971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018767971&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2017.03.020
DO - 10.1016/j.molcel.2017.03.020
M3 - Article
VL - 66
SP - 345-357.e6
JO - Molecular Cell
T2 - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -