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TitleA multivalent adaptor mechanism drives the nuclear import of proteasomes.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateFeb 4, 2026
AuthorsHanna L Brunner / Robert W Kalis / Lorenz Grundmann / Zuzana Hodáková / Zuzana Koskova / Irina Grishkovskaya / Melanie de Almeida / Matthias Hinterndorfer / Hannah Knaudt / Simon Höfflin / Florian Andersch / Harald Kotisch / Achim Dickmanns / Sara Cuylen-Haering / Johannes Zuber / David Haselbach /
PubMed AbstractNuclear protein homeostasis, including transcription factor turnover, critically depends on the nuclear proteasomes that must be imported after cell division. This dynamic process requires AKIRIN2, a ...Nuclear protein homeostasis, including transcription factor turnover, critically depends on the nuclear proteasomes that must be imported after cell division. This dynamic process requires AKIRIN2, a small unstructured protein whose mechanistic role has remained elusive despite its essential function. Using an integrated approach combining protein-wide saturation mutagenesis screens, cryo-EM, and biochemical reconstitution, we characterize AKIRIN2 as a scaffold protein that coordinates the assembly of an importin cluster around the proteasome. AKIRIN2 binds in multiple copies to the 20S proteasome and simultaneously interacts with importin IPO9 and the KPNA2/KPNB1 heterodimer. In the nucleus, RanGTP triggers importin dissociation, releasing the proteasome, while AKIRIN2 undergoes ubiquitin-independent degradation. Our findings reveal how AKIRIN2's multivalency facilitates the recruitment of multiple importins to the proteasome, a critical adaptation for transporting this large macromolecular complex into the nucleus and maintaining the nuclear proteome.
External linksNat Commun / PubMed:41639071 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 4.2 Å
Structure data

EMDB-53246: Consensus refinement: Ternary complex of the human 20S proteasome in complex with Importin-9 and two homo dimers of Akirin-2. Focussed refinement
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-53248, PDB-9qno:
Ternary complex of the human 20S proteasome in complex with Importin-9 and two homodimers of Akirin-2 - focussed refinement on Importin-9 and Akirin-2
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-53264, PDB-9qon:
Ternary complex of the human 20S proteasome in complex with Importin-9 and two homodimers of Akirin-2 - focussed refinement on the alpha subunits, Ipo-9 and Ak2
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-53265: Composite map: Ternary complex of the human 20S proteasome in complex with Importin-9 and two homodimers of Akirin-2
PDB-9qoo: Composite model: Ternary complex of the human 20S proteasome in complex with Importin-9 and two homodimers of Akirin-2
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-53266, PDB-9qop:
Binary complex of human Importin-9 with one homodimer of Akirin-2
Method: EM (single particle) / Resolution: 3.7 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN TRANSPORT / 20S proteasome / 20S / proteasome / nuclear iport / akirin / akirin2 / importin 9 / importin / nuclear import

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