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-Structure paper
タイトル | Structural Basis for the Enzymatic Activity of the HACE1 HECT-Type E3 Ligase Through N-Terminal Helix Dimerization. |
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ジャーナル・号・ページ | Adv Sci (Weinh), Vol. 10, Issue 27, Page e2207672, Year 2023 |
掲載日 | 2023年8月3日 |
著者 | Sunil Singh / Satoru Machida / Nikhil Kumar Tulsian / Yeu Khai Choong / Joel Ng / Srihari Shankar / Yaochen Liu / Krisha Vashdev Chandiramani / Jian Shi / J Sivaraman / |
PubMed 要旨 | HACE1 is an ankyrin repeat (AKR) containing HECT-type E3 ubiquitin ligase that interacts with and ubiquitinates multiple substrates. While HACE1 is a well-known tumor suppressor, its structure and ...HACE1 is an ankyrin repeat (AKR) containing HECT-type E3 ubiquitin ligase that interacts with and ubiquitinates multiple substrates. While HACE1 is a well-known tumor suppressor, its structure and mode of ubiquitination are not understood. The authors present the cryo-EM structures of human HACE1 along with in vitro functional studies that provide insights into how the enzymatic activity of HACE1 is regulated. HACE1 comprises of an N-terminal AKR domain, a middle (MID) domain, and a C-terminal HECT domain. Its unique G-shaped architecture interacts as a homodimer, with monomers arranged in an antiparallel manner. In this dimeric arrangement, HACE1 ubiquitination activity is hampered, as the N-terminal helix of one monomer restricts access to the C-terminal domain of the other. The in vitro ubiquitination assays, hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis, mutagenesis, and in silico modeling suggest that the HACE1 MID domain plays a crucial role along with the AKRs in RAC1 substrate recognition. |
リンク | Adv Sci (Weinh) / PubMed:37537642 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.92 - 4.55 Å |
構造データ | EMDB-34551, PDB-8h8x: EMDB-34586, PDB-8hae: |
由来 |
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キーワード | ANTITUMOR PROTEIN / E3 ubiquitin ligase / tumor suppressor / Post-translational modifier / Protein degradation |