Molecular Determinants for Nuclear Import of Influenza A PB2 by Importin α Isoforms 3 and 7

Structure. 2015 Feb 3;23(2):374-84. doi: 10.1016/j.str.2014.11.015. Epub 2015 Jan 15.

Abstract

Influenza A virus polymerase subunit PB2 is a major virulence determinant implicated in pathogenicity and host adaptation. During cross-species virus transfer from avian to mammalian cells, PB2 switches specificity from importin α3 to α7. This specificity is not recapitulated in vitro, where PB2 binds all importin α isoforms with comparably high affinity. In this study, we investigated the structure, conformational dynamics, and autoinhibition of importin α isoforms 1, 3, and 7 in complex with PB2. Our data suggest that association of PB2 with α3 and α7 is favored by reduced autoinhibition of these isoforms and by the unique structure of the nuclear localization signal (NLS) domain of PB2. We propose that by recruiting importin α3 or α7 in the absence of importin β, PB2 reduces the complexity of adaptor-mediated import to a pseudo-bimolecular reaction, thereby acquiring a kinetic advantage over classical NLS cargos, which form an import complex only when importin α and β are simultaneously available.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Cell Nucleus / metabolism*
  • Crystallization
  • Evolution, Molecular*
  • Humans
  • Models, Molecular*
  • Molecular Sequence Data
  • Nuclear Localization Signals / metabolism*
  • Protein Conformation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • RNA Replicase / metabolism*
  • Sequence Alignment
  • Viral Proteins / metabolism*
  • alpha Karyopherins / chemistry*
  • alpha Karyopherins / metabolism

Substances

  • KPNA4 protein, human
  • KPNA6 protein, human
  • Nuclear Localization Signals
  • PB2 protein, Influenzavirus A
  • Protein Isoforms
  • Viral Proteins
  • alpha Karyopherins
  • RNA Replicase

Associated data

  • PDB/4UAD
  • PDB/4UAE
  • PDB/4UAF