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 a) N-terminal hydrophilic region b) hydrophobic central region composed of 10 repeats c) 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 a) mainly involved in recognition of simple or bipartite NLS motifs b) structurally located within in a helical surface groove c) 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

General

importin alpha subunit phosphoprotein

Properties

SIZE: entity length = 521 aa MW = 58 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: IBB {1-58} MOTIF: nuclear translocation signal {43-52} Ser phosphorylation site {S60} ARM repeat {66-106} ARM repeat {107-149} NLS binding site (major) {137-229} MOTIF: ARM repeat {150-194} ARM repeat {195-233} proline-rich region SITE: 233-236 MOTIF: proline residue (SEVERAL) ARM repeat {234-278} ARM repeat {279-318} NLS binding site (minor) {306-394} MOTIF: ARM repeat {319-360} ARM repeat {361-400} ARM repeat {401-443} ARM repeat {447-485}

Database Correlations

OMIM 602970 UniProt O00629 PFAM correlations Entrez Gene 3840 Kegg hsa:3840

References

UniProt :accession O00629