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  AI-based structure prediction empowers integrative structural analysis of human nuclear pores

Mosalaganti, S., Obarska-Kosinska, A., Siggel, M., Taniguchi, R., Turoňová, B., Zimmerli, C. E., et al. (2022). AI-based structure prediction empowers integrative structural analysis of human nuclear pores. Science, 376(6598): eabm9506. doi:10.1126/science.abm9506.

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Mosalaganti, Shyamal1, 2, 3, Author           
Obarska-Kosinska, Agnieszka1, 4, Author           
Siggel, Marc4, 5, 6, Author           
Taniguchi, Reiya1, 2, Author           
Turoňová, Beata1, 2, Author           
Zimmerli, Christian E.1, 2, Author           
Buczak, Katarzyna2, Author
Schmidt, Florian H.2, Author
Margiotta, Erica1, 2, Author           
Mackmull, Marie-Therese2, Author
Hagen, Wim J. H.2, Author
Hummer, Gerhard5, 7, Author           
Kosinski, Jan2, 4, 6, Author
Beck, Martin1, 2, Author           
Affiliations:
1Department of Molecular Sociology, Max Planck Institute of Biophysics, Max Planck Society, ou_3040395              
2Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany, ou_persistent22              
3Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, USA, ou_persistent22              
4European Molecular Biology Laboratory Hamburg, Hamburg, Germany, ou_persistent22              
5Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
6Centre for Structural Systems Biology, Hamburg, Germany, ou_persistent22              
7Institute of Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany, ou_persistent22              

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 Abstract: Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport. Their intricate 120-megadalton architecture remains incompletely understood. Here, we report a 70-megadalton model of the human NPC scaffold with explicit membrane and in multiple conformational states. We combined artificial intelligence (AI)–based structure prediction with in situ and in cellulo cryo–electron tomography and integrative modeling. We show that linker nucleoporins spatially organize the scaffold within and across subcomplexes to establish the higher-order structure. Microsecond-long molecular dynamics simulations suggest that the scaffold is not required to stabilize the inner and outer nuclear membrane fusion but rather widens the central pore. Our work exemplifies how AI-based modeling can be integrated with in situ structural biology to understand subcellular architecture across spatial organization levels.

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Language(s): eng - English
 Dates: 2021-10-242022-04-222022-06-102022-06-10
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1126/science.abm9506
BibTex Citekey: mosalaganti_ai-based_2022
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Title: Science
  Abbreviation : Science
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Association for the Advancement of Science
Pages: - Volume / Issue: 376 (6598) Sequence Number: eabm9506 Start / End Page: - Identifier: ISSN: 0036-8075
CoNE: https://pure.mpg.de/cone/journals/resource/991042748276600_1