9BV3

M1B Midnolin-Proteasome

This is a non-PDB format compatible entry.

Summary for 9BV3

• Entry DOI: 10.2210/pdb9bv3/pdb
• EMDB information: 44930
• Descriptor: Midnolin, 26S proteasome non-ATPase regulatory subunit 14, 26S proteasome non-ATPase regulatory subunit 8, ... (36 entities in total)
• Functional Keywords: proteasome, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 40
• Total formula weight: 1530508.99

Authors

Gao, J.,Yip, M.C.J.,Shao, S. (deposition date: 2024-05-19, release date: 2025-06-11, Last modification date: 2025-12-24)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.9 Å)