Exploring the "Other" subfamily of HECT E3-ligases for therapeutic intervention

被引:27
作者
Singh, Sunil [1 ]
Ng, Joel [1 ]
Sivaraman, J. [1 ]
机构
[1] Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore
关键词
Other" subfamily HECT; Ubiquitination; Protein Degradation; Cancer; modification; E3 ubiquitin ligase; E3 UBIQUITIN LIGASE; GOLGI MEMBRANE DYNAMICS; INTERACTING PROTEIN 12; ANGELMAN-SYNDROME; TUMOR-SUPPRESSOR; PROTEASOMAL DEGRADATION; INTELLECTUAL DISABILITY; STRUCTURAL BASIS; HEPATOCELLULAR-CARCINOMA; POLYUBIQUITIN CHAINS;
D O I
10.1016/j.pharmthera.2021.107809
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The HECT E3 ligase family regulates key cellular signaling pathways, with its 28 members divided into three sub-families: NEDD4 subfamily (9 members), HERC subfamily (6 members) and "Other" subfamily (13 members). Here, we focus on the less-explored "Other" subfamily and discuss the recent findings pertaining to their biolog-ical roles. The N-terminal regions preceding the conserved HECT domains are significantly diverse in length and sequence composition, and are mostly unstructured, except for short regions that incorporate known substrate-binding domains. In some of the better-characterized "Other" members (e.g., HUWE1, AREL1 and UBE3C), structure analysis shows that the extended region (similar to aa 50) adjacent to the HECT domain affects the sta-bility and activity of the protein. The enzymatic activity is also influenced by interactions with different adaptor proteins and inter/intramolecular interactions. Primarily, the "Other" subfamily members assemble atypical ubiquitin linkages, with some cooperating with E3 ligases from the other subfamilies to form branched ubiquitin chains on substrates. Viruses and pathogenic bacteria target and hijack the activities of "Other" subfamily mem-bers to evade host immune responses and cause diseases. As such, these HECT E3 ligases have emerged as poten-tial candidates for therapeutic drug development. (C) 2021 Elsevier Inc. All rights reserved.
引用
收藏
页数:22
相关论文
共 48 条
  • [31] The role and therapeutic implications of RING-finger E3 ubiquitin ligases in hepatocellular carcinoma
    Yin, Jie
    Zhu, Ji-Min
    Shen, Xi-Zhong
    INTERNATIONAL JOURNAL OF CANCER, 2015, 136 (02) : 249 - 257
  • [32] An activity-based probe developed by a sequential dehydroalanine formation strategy targets HECT E3 ubiquitin ligases
    Xu, Ling
    Fan, Jian
    Wang, Yu
    Zhang, Zhongping
    Fu, Yao
    Li, Yi-Ming
    Shi, Jing
    CHEMICAL COMMUNICATIONS, 2019, 55 (49) : 7109 - 7112
  • [33] E3 ubiquitin ligases and deubiquitinases in colorectal cancer: Emerging molecular insights and therapeutic opportunities
    Kumar, Sunny
    Basu, Malini
    Ghosh, Mrinal K.
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2024, 1871 (08):
  • [34] A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases
    Wang, Zhen
    Liu, Ziheng
    Chen, Xing
    Li, Jingyu
    Yao, Weiyi
    Huang, Shijing
    Gu, Aihong
    Lei, Qun-Ying
    Mao, Ying
    Wen, Wenyu
    NATURE COMMUNICATIONS, 2019, 10 (1)
  • [35] E3 Ubiquitin Ligases: Potential Therapeutic Targets for Skeletal Pathology and Degeneration
    Zeng, Ruiyin
    Xiong, Yuan
    Lin, Ze
    Panayi, Adriana C.
    Sun, Yun
    Cao, Faqi
    Liu, Guohui
    STEM CELLS INTERNATIONAL, 2022, 2022
  • [36] The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders
    Owais, Asia
    Mishra, Rama K.
    Kiyokawa, Hiroaki
    CANCERS, 2020, 12 (08) : 1 - 19
  • [37] Arabidopsis HECT and RING-type E3 Ligases Promote MAPKKK18 Degradation to Regulate Abscisic Acid Signaling
    Tajdel-Zielinska, Malgorzata
    Janicki, Maciej
    Marczak, Malgorzata
    Ludwikow, Agnieszka
    PLANT AND CELL PHYSIOLOGY, 2024, 65 (03) : 390 - 404
  • [38] E3 Ligases and COVID-19: Insights into Viral Control and Therapeutic Potential
    Mishra, Mukul
    Khan, Deeba
    Islam, Sehbanul
    BIOCELL, 2025, 49 (01) : 127 - 147
  • [39] Role of the Mitochondrial E3 Ubiquitin Ligases as Possible Therapeutic Targets in Cancer Therapy
    Di Gregorio, Jacopo
    Appignani, Martina
    Flati, Vincenzo
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (24)
  • [40] Crystal structures of two bacterial HECT-like E3 ligases in complex with a human E2 reveal atomic details of pathogen-host interactions
    Lin, David Yin-wei
    Diao, Jianbo
    Chen, Jue
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (06) : 1925 - 1930