Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone

Padavannil, Abhilash; Sarkar, Prithwijit; Kim, Seung Joong; Çağatay, Tolga; Jiou, Jenny; Brautigam, Chad A.; Tomchick, Diana R.; Šali, Andrej; D’Arcy, Sheena; Chook, Yuh Min

doi:10.7554/elife.43630

Cited by 51 publications

(92 citation statements)

References 85 publications

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“…The fact that DNA binding activities of Tb RAP1 rely on the same peptide that signals for nuclear import suggests that deposition of Tb RAP1 to the telomere chromatin may be regulated. A recent structural study showed that importin-9 binds histone H2A-H2B and functions more like a storage chaperon ( 37 ). After H2A-H2B is transported into the nucleus, RanGTP does not directly dissociate the importin-9 and H2A-H2B interaction.…”

Section: Discussionmentioning

confidence: 99%

Tb RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

et al. 2020

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Localization of Repressor Activator Protein 1 (RAP1) to the telomere is essential for its telomeric functions. RAP1 homologs either directly bind the duplex telomere DNA or interact with telomere-binding proteins. We find that Trypanosoma brucei RAP1 relies on a unique double-stranded DNA (dsDNA) binding activity to achieve this goal. T. brucei causes human sleeping sickness and regularly switches its major surface antigen, variant surface glycoprotein (VSG), to evade the host immune response. VSGs are monoallelically expressed from subtelomeres, and TbRAP1 is essential for VSG regulation. We identify dsDNA and single-stranded DNA binding activities in TbRAP1, which require positively charged 737RKRRR741 residues that overlap with TbRAP1’s nuclear localization signal in the MybLike domain. Both DNA binding activities are electrostatics-based and sequence nonspecific. The dsDNA binding activity can be substantially diminished by phosphorylation of two 737RKRRR741-adjacent S residues and is essential for TbRAP1’s telomere localization, VSG silencing, telomere integrity, and cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Tb RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

et al. 2020

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“…These NLS-like peptides could be imported into the nucleus and were found to bind Impβ, Kap114 and Kap121 [ 47 , 51 ]. However, deletions of H2A and H2B N-terminal tails did not abolish the nuclear import of H2A or H2B in yeast strains and did not affect the binding affinity with Imp9, suggesting the histone fold-domain of H2A–H2B is important for binding importins [ 25 , 56 , 57 ].…”

Section: Nuclear Import Of Core Histones H2a and H2bmentioning

confidence: 99%

“…The structure of Imp9 bound to the H2A–H2B heterodimer showed only a few residues of the N-terminal tail of H2B binding to the importin, and removal of the H2B tail did not decrease the affinity of H2A–H2B for Imp9 ( Figure 4A,C ) [ 25 ]. Instead, the N- and C-terminal regions of Imp9 clamp the histone fold domain and shield H2A–H2B from promiscuous interactions in the cytoplasm, acting as a histone-chaperone ( Figure 4A,B ) [ 25 ]. At the N-terminus of Imp9, acid residues in the inner concave surface of Imp9 (HEAT repeats 2–5) interact with basic surfaces of the H2A–H2B core domain, the same basic residues that bind DNA in the nucleosome ( Figure 4B ).…”

Section: Nuclear Import Of Core Histones H2a and H2bmentioning

confidence: 99%

Nuclear import of histones

Bernardes

Chook

2020

Biochemical Society Transactions

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The transport of histones from the cytoplasm to the nucleus of the cell, through the nuclear membrane, is a cellular process that regulates the supply of new histones in the nucleus and is key for DNA replication and transcription. Nuclear import of histones is mediated by proteins of the karyopherin family of nuclear transport receptors. Karyopherins recognize their cargos through linear motifs known as nuclear localization/export sequences or through folded domains in the cargos. Karyopherins interact with nucleoporins, proteins that form the nuclear pore complex, to promote the translocation of their cargos into the nucleus. When binding to histones, karyopherins not only function as nuclear import receptors but also as chaperones, protecting histones from non-specific interactions in the cytoplasm, in the nuclear pore and possibly in the nucleus. Studies have also suggested that karyopherins might participate in histones deposition into nucleosomes. In this review we describe structural and biochemical studies from the last two decades on how karyopherins recognize and transport the core histone proteins H3, H4, H2A and H2B and the linker histone H1 from the cytoplasm to the nucleus, which karyopherin is the major nuclear import receptor for each of these histones, the oligomeric state of histones during nuclear import and the roles of post-translational modifications, histone-chaperones and RanGTP in regulating these nuclear import pathways.

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“…Cargos are recognized by importins-α/β through nuclear localization signals (NLSs), usually made of basic or hydrophobic motifs [13,14]. Additionally to the interaction with the NLS motifs, recent karyopherins-β/cargo-protein structures have demonstrated that these complexes are dependent on multiple interactions, mediated through intricate 3D interfaces which involve residues well beyond the NLS peptide stretch [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Differential Behaviours and Preferential Bindings of Influenza Nucleoproteins on Importins-α

Donchet

Vassal-Stermann

Gérard

et al. 2020

Viruses

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Influenza viruses are negative single-stranded RNA viruses with nuclear transcription and replication. They enter the nucleus by using the cellular importin-α/-β nuclear import machinery. Influenza nucleoproteins from influenza A, B, C and D viruses possess a nuclear localization signal (NLS) localized on an intrinsically disordered extremity (NPTAIL). In this paper, using size exclusion chromatography (SEC), SEC-multi-angle laser light scattering (SEC-MALLS) analysis, surface plasmon resonance (SPR) and fluorescence anisotropy, we provide the first comparative study designed to dissect the interaction between the four NPTAILs and four importins-α identified as partners. All interactions between NPTAILs and importins-α have high association and dissociation rates and present a distinct and specific behaviour. D/NPTAIL interacts strongly with all importins-α while B/NPTAIL shows weak affinity for importins-α. A/NPTAIL and C/NPTAIL present preferential importin-α partners. Mutations in B/NPTAIL and D/NPTAIL show a loss of importin-α binding, confirming key NLS residues. Taken together, our results provide essential highlights of this complex translocation mechanism.

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Importin-9 wraps around the H2A-H2B core to act as nuclear importer and histone chaperone

Cited by 51 publications

References 85 publications

Tb RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

Tb RAP1 has an unusual duplex DNA binding activity required for its telomere localization and VSG silencing

Nuclear import of histones

Differential Behaviours and Preferential Bindings of Influenza Nucleoproteins on Importins-α

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