9NKG

Structure of substrate engaged MIDN-bound human 26S proteasome, EB-MIDN (Composite map)

This is a non-PDB format compatible entry.

Summary for 9NKG

• Entry DOI: 10.2210/pdb9nkg/pdb
• EMDB information: 49508
• Related PRD ID: PRD_000907
• Descriptor: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (39 entities in total)
• Functional Keywords: ubiquitin-indepedent, proteasome, midnolin, midn-bound 26s complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 48
• Total formula weight: 1720565.24

Authors

Peddada, N.,Beutler, B. (deposition date: 2025-02-28, release date: 2025-05-07, Last modification date: 2025-05-21)

Primary citation

Peddada, N.,Zhong, X.,Yin, Y.,Lazaro, D.R.,Wang, J.,Lyon, S.,Choi, J.H.,Bai, X.C.,Moresco, E.M.Y.,Beutler, B.
Structural insights into the ubiquitin-independent midnolin-proteasome pathway.
Proc.Natl.Acad.Sci.USA, 122:e2505345122-e2505345122, 2025

PubMed Abstract: The protein midnolin (MIDN) augments proteasome activity in lymphocytes and dramatically facilitates the survival and proliferation of B-lymphoid malignancies. MIDN binds both to proteasomes and to substrates, but the mode of interaction with the proteasome is unknown, and the mechanism by which MIDN facilitates substrate degradation in a ubiquitin-independent manner is incompletely understood. Here, we present cryoelectron microscopy (cryo-EM) structures of the substrate-engaged, MIDN-bound human proteasome in two conformational states. MIDN induces proteasome conformations similarly to ubiquitinated substrates by using its ubiquitin-like domain to bind to the deubiquitinase RPN11 (PSMD14). By simultaneously binding to RPN1 (PSMD2) with its C-terminal α-helix, MIDN positions its substrate-carrying Catch domain above the proteasome ATPase channel through which substrates are translocated before degradation. Our findings suggest that both ubiquitin-like domain and C-terminal α-helix must bind to the proteasome for MIDN to stimulate proteasome activity.

PubMed: 40339123
DOI: 10.1073/pnas.2505345122

Experimental method

ELECTRON MICROSCOPY (2.8 Å)