Alternative titles; symbols
HGNC Approved Gene Symbol: KPNA1
Cytogenetic location: 3q21.1 Genomic coordinates (GRCh38): 3:122,421,902-122,514,939 (from NCBI)
Cortes et al. (1994) used the 2-hybrid protein interaction systems to isolate a protein that specifically interacts with RAG1 (179615). The genes RAG1 and RAG2 (179616) are able to activate V(D)J recombination when transfected into fibroblasts. Further, knockout mice for these 2 loci lack B and T cells. Several other ubiquitously expressed proteins are thought to be recruited in the recombination process. Among these are the genes affected in severe combined immune deficiency (e.g., 600899) and genes involved in ds-DNA break repair. The human cDNA identified by Cortes et al. (1994) encodes a 489-amino acid polypeptide that shows striking similarity to the yeast SRP1 protein, a mutant allele which can suppress a mutation of RNA polymerase I. The authors obtained human and mouse cDNA sequences which are 98% identical as proteins. When RAG1 and human SRP1 were cotransfected into 293T cells a stable complex of the 2 was observed. The authors speculated that because SRP1 appears to be bound to the nuclear envelope, the interaction with RAG1 may serve to localize that protein to the envelope as well.
Using an in vitro import assay based on permeabilized HeLa cells to study the import substrate specificity of all ubiquitously expressed importins, including KPNA1, Kohler et al. (1999) found that all importins tested were able to transport HNRNPK (600712) and PCAF (602303), in addition to the standard test substrates, but only KPNA4 (601892) showed a strong preference for the import of GDP/GTP exchange factor RCC1 (179710), which is exclusively located inside the nucleus. When HNRNPK, PCAF, and RCC1 were offered with a competing substrate nucleoplasmin (164040), they found that substrate binding was diminished or abolished in some importins and retained in others.
By Western blot analysis and in vitro binding assays, Ma and Cao (2006) found that nuclear translocation of STAT3 (102582) and STAT1 (600555) is mediated by binding of human KPNA1 and KPNA6.
King et al. (2006) showed that integral inner nuclear membrane proteins possess basic sequence motifs that resemble classical nuclear localization signals. These sequences can mediate direct binding to karyopherin-alpha and are essential for the passage of integral membrane proteins to the inner nuclear membrane. Furthermore, karyopherin-alpha, karyopherin-beta-1 (602738), and the Ran GTPase cycle are required for inner nuclear membrane targeting, underscoring parallels between mechanisms governing the targeting of integral inner nuclear membrane proteins and soluble nuclear transport. King et al. (2006) also provided evidence that specific nuclear pore complex proteins contribute to this process, suggesting a role for signal-mediated alterations in the nuclear pore complex to allow for passage of inner nuclear membrane proteins along the pore membrane.
By fluorescence in situ hybridization, Ayala-Madrigal et al. (2000) mapped the human KPNA1 gene to chromosome 3q21.
Conti et al. (1998) reported the crystal structure of a 50-kD fragment of the 60-kD yeast karyopherin alpha, in the absence and presence of a monopartite nuclear localization signal (NLS) peptide at 2.2-angstrom and 2.8-angstrom resolution, respectively. The structure showed a tandem array of 10 armadillo repeats, organized in a right-handed superhelix of helices. Binding of the NLS peptide occurred at 2 sites within a helical surface groove. The structure reveals the determinants of NLS specificity and suggested a model for the recognition of bipartite NLSs.
Ayala-Madrigal, M. L., Doerr, S., Ramirez-Duenas, M. L., Hansmann, I. Assignment of karyopherin alpha 1 (KPNA1) to human chromosome band 3q21 by in situ hybridization. Cytogenet. Cell Genet. 90: 58-59, 2000. [PubMed: 11060446] [Full Text: https://doi.org/10.1159/000015661]
Conti, E., Uy, M., Leighton, L., Blobel, G., Kuriyan, J. Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha. Cell 94: 193-204, 1998. [PubMed: 9695948] [Full Text: https://doi.org/10.1016/s0092-8674(00)81419-1]
Cortes, P., Ye, Z.-S., Baltimore, D. RAG-1 interacts with the repeated amino acid motif of the human homologue of the yeast protein SRP1. Proc. Nat. Acad. Sci. 91: 7633-7637, 1994. [PubMed: 8052633] [Full Text: https://doi.org/10.1073/pnas.91.16.7633]
King, M. C., Lusk, C. P., Blobel, G. Karyopherin-mediated import of integral inner nuclear membrane proteins. Nature 442: 1003-1007, 2006. [PubMed: 16929305] [Full Text: https://doi.org/10.1038/nature05075]
Kohler, M., Speck, C., Christiansen, M., Bischoff, F. R., Prehn, S., Haller, H., Gorlich, D., Hartmann, E. Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Molec. Cell. Biol. 19: 7782-7791, 1999. [PubMed: 10523667] [Full Text: https://doi.org/10.1128/MCB.19.11.7782]
Ma, J., Cao, X. Regulation of Stat3 nuclear import by importin alpha-5 and importin alpha-7 via two different functional sequence elements. Cell. Signal. 18: 1117-1126, 2006. [PubMed: 16298512] [Full Text: https://doi.org/10.1016/j.cellsig.2005.06.016]