bims-nucpor 2022-09-18 papers

Issue of 2022‒09‒18
five papers selected by
Sara Mingu
Johannes Gutenberg University

Cold Spring Harb Perspect Biol. 2022 Sep 12. pii: a041264. [Epub ahead of print]

Structure and Function of the Nuclear Pore Complex.

Stefan Petrovic, George W Mobbs, Christopher J Bley, Si Nie, Alina Patke, André Hoelz.

The nucleus, a genome-containing organelle eponymous of eukaryotes, is enclosed by a double membrane continuous with the endoplasmic reticulum. The nuclear pore complex (NPC) is an ∼110-MDa, ∼1000-protein channel that selectively transports macromolecules across the nuclear envelope and thus plays a central role in the regulated flow of genetic information from transcription to translation. Its size, complexity, and flexibility have hindered determination of atomistic structures of intact NPCs. Recent studies have overcome these hurdles by combining biochemical reconstitution and docking of high-resolution structures of NPC subcomplexes into cryo-electron tomographic reconstructions with biochemical and physiological validation. Here, we provide an overview of the near-atomic composite structure of the human NPC, a milestone toward unlocking a molecular understanding of mRNA export, NPC-associated diseases, and viral host-pathogen interactions, serving as a paradigm for studying similarly large complexes.

DOI: https://doi.org/10.1101/cshperspect.a041264

Biology (Basel). 2022 Jul 04. pii: 1009. [Epub ahead of print]11(7):

Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.

Amandeep Girdhar, Lin Guo.

RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid-liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases.

Keywords: ALS; FUS; Kapβ2; TDP-43; liquid–liquid phase separation; nuclear import receptor

DOI: https://doi.org/10.3390/biology11071009

Nucleus. 2022 Dec;13(1): 221-235

A-type lamins involvement in transport and implications in cancer?

Nicholas R Scott, Sapun H Parekh.

Nuclear lamins and transport are intrinsically linked, but their relationship is yet to be fully unraveled. A multitude of complex, coupled interactions between lamins and nucleoporins (Nups), which mediate active transport into and out of the nucleus, combined with well documented dysregulation of lamins in many cancers, suggests that lamins and nuclear transport may play a pivotal role in carcinogenesis and the preservation of cancer. Changes of function related to lamin/Nup activity can principally lead to DNA damage, further increasing the genetic diversity within a tumor, which could lead to the reduction the effectiveness of antineoplastic treatments. This review discusses and synthesizes different connections of lamins to nuclear transport and offers a number of outlook questions, the answers to which could reveal a new perspective on the connection of lamins to molecular transport of cancer therapeutics, in addition to their established role in nuclear mechanics.

Keywords: A-type lamins; cancer; lamin A/C; membrane diffusion; nuclear trafficking; nuclear transport; nucleoporins; nucleus; size dependent transport; transport in cancer

DOI: https://doi.org/10.1080/19491034.2022.2118418

Nucleic Acids Res. 2022 Sep 13. pii: gkac754. [Epub ahead of print]

Three tRNA nuclear exporters in S. cerevisiae: parallel pathways, preferences, and precision.

Kunal Chatterjee, William A Marshall, Anita K Hopper.

tRNAs that are transcribed in the nucleus are exported to the cytoplasm to perform their iterative essential function in translation. However, the complex set of tRNA post-transcriptional processing and subcellular trafficking steps are not completely understood. In particular, proteins involved in tRNA nuclear export remain unknown since the canonical tRNA nuclear exportin, Los1/Exportin-t, is unessential in all tested organisms. We previously reported that budding yeast Mex67-Mtr2, a mRNA nuclear exporter, co-functions with Los1 in tRNA nuclear export. Here we employed in vivo co-purification of tRNAs with endogenously expressed nuclear exporters to document that Crm1 also is a bona fide tRNA nuclear exporter. We document that Los1, Mex67-Mtr2 and Crm1 possess individual tRNA preferences for forming nuclear export complexes with members of the 10 families of intron-containing pre-tRNAs. Remarkably, Mex67-Mtr2, but not Los1 or Crm1, is error-prone, delivering tRNAs to the cytoplasm prior to 5' leader removal. tRNA retrograde nuclear import functions to monitor the aberrant leader-containing spliced tRNAs, returning them to the nucleus where they are degraded by 3' to 5' exonucleases. Overall, our work identifies a new tRNA nuclear exporter, uncovers exporter preferences for specific tRNA families, and documents contribution of tRNA nuclear import to tRNA quality control.

DOI: https://doi.org/10.1093/nar/gkac754

Proc Natl Acad Sci U S A. 2022 Sep 20. 119(38): e2207177119

Structure of IMPORTIN-4 bound to the H3-H4-ASF1 histone-histone chaperone complex.

Natália Elisa Bernardes, Ho Yee Joyce Fung, Yang Li, Zhe Chen, Yuh Min Chook.

IMPORTIN-4, the primary nuclear import receptor of core histones H3 and H4, binds the H3-H4 dimer and histone chaperone ASF1 prior to nuclear import. However, how H3-H3-ASF1 is recognized for transport cannot be explained by available crystal structures of IMPORTIN-4-histone tail peptide complexes. Our 3.5-Å IMPORTIN-4-H3-H4-ASF1 cryoelectron microscopy structure reveals the full nuclear import complex and shows a binding mode different from suggested by previous structures. The N-terminal half of IMPORTIN-4 clamps the globular H3-H4 domain and H3 αN helix, while its C-terminal half binds the H3 N-terminal tail weakly; tail contribution to binding energy is negligible. ASF1 binds H3-H4 without contacting IMPORTIN-4. Together, ASF1 and IMPORTIN-4 shield nucleosomal H3-H4 surfaces to chaperone and import it into the nucleus where RanGTP binds IMPORTIN-4, causing large conformational changes to release H3-H4-ASF1. This work explains how full-length H3-H4 binds IMPORTIN-4 in the cytoplasm and how it is released in the nucleus.

Keywords: histones; importin; karyopherins; nuclear import; nucleosome

DOI: https://doi.org/10.1073/pnas.2207177119