Nuclear pore dysfunction and disease: a complex opportunity

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 21, 2024

The separation of genetic material from bulk cytoplasm has enabled the evolution increasingly complex organisms, allowing for development sophisticated forms life. However, this complexity created new categories dysfunction, including those related to movement between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions nuclear integrity transport are detrimental cell survival. This particularly true in post-mitotic neurons, where pore injury errors strongly associated with neurodegenerative disease. review, we summarize current understanding biology physiological pathological contexts discuss potential therapeutic approaches addressing dysfunctional transport.

Language: Английский

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AlphaFold2 as a replacement for solution NMR structure determination of small proteins: Not so fast!

Journal of Magnetic Resonance, Journal Year: 2024, Volume and Issue: 364, P. 107725 - 107725

Published: June 19, 2024

The determination of a protein's structure is often first step towards the development mechanistic understanding its function. Considerable advances in computational protein prediction have been made recent years, with AlphaFold2 (AF2) emerging as primary tool used by researchers for this purpose. While AF2 generally predicts accurate structures folded proteins, we present here case where incorrectly small, and compact high confidence. This protein, pro-interleukin-18 (pro-IL-18), precursor cytokine IL-18. Interestingly, pro-IL-18 predicted matches that mature cytokine, not corresponding experimentally determined pro-form protein. Thus, while holds immense promise addressing problems biophysics, there still need experimental determination, even context small well-folded, globular proteins.

Language: Английский

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Integrative spatiotemporal modeling of biomolecular processes: Application to the assembly of the nuclear pore complex

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 14, 2025

Dynamic processes involving biomolecules are essential for the function of cell. Here, we introduce an integrative method computing models these based on multiple heterogeneous sources information, including time-resolved experimental data and physical dynamic processes. First, each time point, a set coarse compositional structural heterogeneity is computed (heterogeneity models). Second, model, static structure (a snapshot model). Finally, selected connected into series trajectories that optimize likelihood both transitions between them trajectory The demonstrated by application to assembly process human nuclear pore complex in context reforming envelope during mitotic cell division, live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy–calibrated quantitative live imaging, model fully assembled complex. Modeling improves precision over modeling alone. applicable wide range time-dependent systems biology available broader scientific community through implementation open source Integrative Platform (IMP) software.

Language: Английский

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DPAM: A domain parser for AlphaFold models

Protein Science, Journal Year: 2022, Volume and Issue: 32(2)

Published: Dec. 21, 2022

The recent breakthroughs in structure prediction, where methods such as AlphaFold demonstrated near-atomic accuracy, herald a paradigm shift structural biology. 200 million high-accuracy models released the Database are expected to guide protein science coming decades. Partitioning these into domains and assigning them an evolutionary hierarchy provide efficient way gain functional insights proteins. However, classifying large number of predicted structures challenges infrastructure current classifications, including our Evolutionary Classification Domains (ECOD). Better computational tools urgently needed parse classify from automatically. Here we present Domain Parser for Models (DPAM) that can automatically recognize globular based on inter-residue distances 3D structures, aligned errors, ECOD found by sequence (HHsuite) (Dali) similarity searches. Based benchmark 18,759 models, demonstrate DPAM 98.8% assign correct boundaries 87.5%, significantly outperforming structure-based domain parsers homology-based assignment using HHsuite or Dali. Application massive will enable classification domains, providing contexts facilitating studies.

Language: Английский

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Nuclear export of pre-60S particles through the nuclear pore complex

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 411 - 418

Published: May 31, 2023

Language: Английский

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