importin alpha-4 subunit (karyopherin alpha-4 subunit, KPNA4, Qip1 protein)

Function

• nuclear protein import as an adapter protein for nuclear receptor KPNB1
• binds specifically & directly to substrates containing either a simple or bipartite NLS motif
• docking of the importin/substrate complex to the nuclear pore complex is mediated by KPNB1 through binding to nucleoporin FxFG repeats
• the complex is subsequently translocated through the pore by an energy requiring, Ran- dependent mechanism
• at the nucleoplasmic side of the nuclear pore complex, Ran binds to importin-beta & the 3 components separate
• importin-alpha & importin-beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin
• directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- & GDP-bound forms of Ran between the cytoplasm & nucleus
• forms a complex with importin subunit beta-1

Structure

• consists of
  • N-terminal hydrophilic region
  • hydrophobic central region composed of 10 repeats
  • short hydrophilic C-terminus
• N-terminal hydrophilic region contains the importin beta binding domain (IBB domain), which is sufficient for binding importin beta & essential for nuclear protein import
• the IBB domain is thought to act as an intrasteric autoregulatory sequence by interacting with the internal autoinhibitory NLS
• binding of KPNB1 probably overlaps the internal NLS & contributes to a high affinity for cytoplasmic NLS- containing cargo substrates
• after dissociation of the importin/substrate complex in the nucleus, the internal autohibitory NLS contributes to a low affinity for nuclear NLS- containing proteins (putative)
• the major & minor NLS binding sites
  • mainly involved in recognition of simple or bipartite NLS motifs
  • structurally located within in a helical surface groove
  • they contain several conserved Trp & Asn of the corresponding 3rd helices (H3) of ARM repeats which mainly contribute to binding
• belongs to the importin alpha family
• contains 10 ARM repeats
• contains 1 IBB domain

Compartment

cytoplasm, nucleus

Expression

• highly expressed in testis, ovary, small intestine, heart, skeletal muscle, lung & pancreas
• barely detectable in kidney, thymus, colon & peripheral blood leukocytes

Pathology

• in vitro, mediates nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS

More general terms

• importin alpha subunit
• phosphoprotein

Additional terms

• importin complex (NLS-binding protein)

Database

• OMIM: https://mirror.omim.org/entry/602970
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:3840
• UniProt: http://www.uniprot.org/uniprot/O00629.html
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=3840