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Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate.

ABSTRACT: CRM1 (also known as exportin 1 or Xpo1) is the most versatile nuclear export receptor (exportin) that carries a broad range of proteins and ribonucleoproteins from the nucleus to the cytoplasm through the nuclear pore complex. The majority of the export substrates of CRM1 contain a short peptide sequence, so-called leucine-rich nuclear export signal (NES), which typically harbor four or five characteristically spaced hydrophobic residues. The transport directionality is determined by the small GTPase Ran and Ran-binding proteins that control the binding and dissociation of cargo. Here we review recent structural studies that advanced understanding of how NES is specifically recognized by CRM1 in the nucleus, and how NES is rapidly dissociated from CRM1 in the cytoplasm.

SUBMITTER: Koyama M

PROVIDER: S-EPMC4629651 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate.

Koyama Masako M Matsuura Yoshiyuki Y

Biophysics (Nagoya-shi, Japan) 20121130

CRM1 (also known as exportin 1 or Xpo1) is the most versatile nuclear export receptor (exportin) that carries a broad range of proteins and ribonucleoproteins from the nucleus to the cytoplasm through the nuclear pore complex. The majority of the export substrates of CRM1 contain a short peptide sequence, so-called leucine-rich nuclear export signal (NES), which typically harbor four or five characteristically spaced hydrophobic residues. The transport directionality is determined by the small G ...[more]

PMID: 27493531

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Project description:After receptor-mediated endocytosis and endosomal escape, adenoviral capsids can travel via microtubule organizing centers to the nuclear envelope. Upon capsid disassembly, viral genome import into nuclei of interphase cells then occurs through nuclear pore complexes, involving the nucleoporins Nup214 and Nup358. Import also requires the activity of the classic nuclear export receptor CRM1, as it is blocked by the selective inhibitor leptomycin B. We have now used artificially enucleated as well as mitotic cells to analyze the role of an intact nucleus in different steps of the viral life cycle. In enucleated U2OS cells, viral capsids traveled to the microtubule organizing center, whereas their removal from this complex was blocked, suggesting that this step required nuclear factors. In mitotic cells, on the other hand, CRM1 promoted capsid disassembly and genome release, suggesting a role of this protein that does not require intact nuclear envelopes or nuclear pore complexes and is distinct from its function as a nuclear export receptor. Similar to enucleation, inhibition of CRM1 by leptomycin B also leads to an arrest of adenoviral capsids at the microtubule organizing center. In a small-scale screen using leptomycin B-resistant versions of CRM1, we identified a mutant, CRM1 W142A P143A, that is compromised with respect to adenoviral capsid disassembly in both interphase and mitotic cells. Strikingly, this mutant is capable of exporting cargo proteins out of the nucleus of living cells or digitonin-permeabilized cells, pointing to a role of the mutated region that is not directly linked to nuclear export. IMPORTANCE A role of nucleoporins and of soluble transport factors in adenoviral genome import into the nucleus of infected cells in interphase has previously been established. The nuclear export receptor CRM1 promotes genome import, but its precise function is not known. Using enucleated and mitotic cells, we showed that CRM1 does not simply function by exporting a crucial factor out of the nucleus that would then trigger capsid disassembly and genome import. Instead, CRM1 has an export-independent role, a notion that is also supported by a mutant, CRM1 W142A P143A, which is export competent but deficient in viral capsid disassembly, in both interphase and mitotic cells.

Dataset Information

Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate.

Publications

Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate.

Similar Datasets

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