9BV1

M2A Midnolin-Proteasome (translocating)

9BV1 の概要

• エントリーDOI: 10.2210/pdb9bv1/pdb
• EMDBエントリー: 44927
• 分子名称: 26S proteasome non-ATPase regulatory subunit 1, 26S proteasome non-ATPase regulatory subunit 8, 26S proteasome complex subunit SEM1, ... (37 entities in total)
• 機能のキーワード: proteasome, nuclear protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 40
• 化学式量合計: 1523929.64

構造登録者

Gao, J.,Yip, M.C.J.,Shao, S. (登録日: 2024-05-19, 公開日: 2025-06-11, 最終更新日: 2025-12-24)

主引用文献

Nardone, C.,Gao, J.,Seo, H.S.,Mintseris, J.,Ort, L.,Yip, M.C.J.,Negasi, M.,Besschetnova, A.K.,Kamitaki, N.,Gygi, S.P.,Dhe-Paganon, S.,Munshi, N.C.,Fulciniti, M.,Greenberg, M.E.,Shao, S.,Elledge, S.J.,Gu, X.
Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.
Mol.Cell, 85:2597-2609.e11, 2025

PubMed Abstract: The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2/Rpn1 binds to ubiquitinated or ubiquitin-like (Ubl) proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin's activity is confined to the nucleus. Likewise, PSMD14/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by stabilizing the transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.

PubMed: 40532701
DOI: 10.1016/j.molcel.2025.05.030

実験手法

ELECTRON MICROSCOPY (3.1 Å)