Alternative titles; symbols
HGNC Approved Gene Symbol: SNUPN
Cytogenetic location: 15q24.2 Genomic coordinates (GRCh38): 15:75,598,086-75,626,461 (from NCBI)
The nuclear import of the spliceosomal snRNPs U1, U2, U4 and U5 is dependent on the presence of a complex nuclear localization signal (NLS). The latter is composed of the 5-prime-2,2,7-terminal trimethylguanosine (m3G) cap structure of the U snRNA and the Sm core domain.
Huber et al. (1998) described the isolation and cDNA cloning of a 45-kD protein, termed snurportin-1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin-1 enhanced the m3G-cap-dependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor. The m3G-cap and not the Sm core NLS appeared to be recognized by snurportin-1, indicating that at least 2 distinct import receptors interact with the complex snRNP NLS. Snurportin-1 is a nuclear import receptor which contains an N-terminal importin-beta-binding (IBB) domain, essential for function, and a C-terminal m3G-cap-binding region with no structural similarity to the arm repeat domain of importin-alpha (KPNA2; 600685). Using a UV cross-linking assay, Huber et al. (1998) identified snurportin-1 as a protein capable of binding m3G-cap. The protein was isolated, fragmented into peptides, and microsequenced. Corresponding ESTs were identified from online databases, and assembled into a full-length cDNA predicted to encode a 360-amino acid protein with a molecular weight of 41 kD.
Narayanan et al. (2002) reported that a mutant snurportin construct lacking the IBB domain, but containing an intact TMG cap-binding domain, localized primarily to the nucleus, whereas full-length snurportin localized to the cytoplasm. Snurportin interacted with SMN (600354), Gemin3 (606168), Sm snRNPs, and importin-beta (602738). In the presence of ribonucleases, the interactions with SMN and Sm proteins were abolished, suggesting that snRNAs may mediate this interplay. Cell fractionation studies showed that snurportin bound preferentially to cytoplasmic SMN complexes. Additionally, SMN directly interacted with importin-beta in a GST-pull-down assay, suggesting that the SMN complex may represent the Sm core NLS receptor predicted by previous studies. The authors concluded that, following Sm protein assembly, the SMN complex may persist until the final stages of cytoplasmic snRNP maturation, and may provide somatic cell RNPs with an alternative NLS.
Crystal Structure
Dong et al. (2009) presented a 2.9-angstrom resolution crystal structure of CRM1 (602559) bound to snurportin-1. Snurportin-1 binds CRM1 in a bipartite manner by means of an N-terminal leucine-rich nuclear export signal (LR-NES) and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between 2 CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues, and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin-1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.
Monecke et al. (2009) presented the crystal structure of the SPN1-CRM1-RanGTP (see 601179) export complex at 2.5-angstrom resolution. SPN1 is a nuclear import adaptor for cytoplasmically assembled, m3G-capped spliceosomal U snRNPs. The structure showed how CRM1 can specifically return the cargo-free form of SPN1 to the cytoplasm. The extensive contact area includes 5 hydrophobic residues at the SPN1 amino terminus that dock into a hydrophobic cleft of CRM1, as well as numerous hydrophilic contacts of CRM1 to m3G cap-binding domain and carboxyl-terminal residues of SPN1. Monecke et al. (2009) concluded that RanGTP promotes cargo binding to CRM1 solely through long-range conformational changes in the exportin.
Dong, X., Biswas, A., Suel, K. E., Jackson, L. K., Martinez, R., Gu, H., Chook, Y. M. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature 458: 1136-1141, 2009. Note: Erratum: Nature 461: 550 only, 2009. [PubMed: 19339969] [Full Text: https://doi.org/10.1038/nature07975]
Huber, J., Cronshagen, U., Kadokura, M., Marshallsay, C., Wada, T., Sekine, M., Luhrmann, R. Snurportin1, an m3G-cap-specific nuclear import receptor with a novel domain structure. EMBO J. 17: 4114-4126, 1998. [PubMed: 9670026] [Full Text: https://doi.org/10.1093/emboj/17.14.4114]
Monecke, T., Guttler, T., Neumann, P., Dickmanns, A., Gorlich, D., Ficner, R. Crystal structure of the nuclear export receptor CRM1 in complex with snurportin 1 and RanGTP. Science 324: 1087-1091, 2009. [PubMed: 19389996] [Full Text: https://doi.org/10.1126/science.1173388]
Narayanan, U., Ospina, J. K., Frey, M. R., Hebert, M. D., Matera, A. G. SMN, the spinal muscular atrophy protein, forms a pre-import snRNP complex with snurportin1 and importin beta. Hum. Molec. Genet. 11: 1785-1795, 2002. [PubMed: 12095920] [Full Text: https://doi.org/10.1093/hmg/11.15.1785]