Disease relevance of SRP1

• Thus, Yap1 is not directly involved in SRP1 induction by hypoxia, but is necessary to counteract the Ord1 effect [1].
• NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein [2].

High impact information on SRP1

• Importin shows 44% sequence identity with SRP1p, a protein associated with the yeast nuclear pore complex [3].
• Like the importin-beta subunit of the nuclear import receptor, Vpr also interacts with the yeast importin-alpha subunit and nucleoporins [4].
• Significantly, symmetric deletions caused mild reductions in Kap95-Kap60-mediated import rates, but virtually abolished Kap104 import [5].
• Kap95 (importin-beta) was necessary for nuclear entry, but not Kap60 (importin-alpha), and exportin Msn5 was required for nuclear exit [6].
• Nup2p binds Kap60p more strongly than NLSs and accelerates release of NLSs from Kap60p [7].

Biological context of SRP1

• Consistent with this conclusion, both yrb1ts mutations display deleterious genetic interactions with mutations in many other genes involved in nucleocytoplasmic transport, including SRP1 (alpha-importin) and several beta-importin family members [8].
• Nup2p is located at the nuclear side of the central gated channel of the NPC and provides a binding site for Srp1p via its amino-terminal domain [9].
• In the yeast Saccharomyces ceresivisiae, the essential gene CSE1 encodes a Cas homologue that exports the yeast importin-alpha protein Srp1p/Kap60p from the nucleus [10].
• The tumor suppressor gene overgrown hematopoietic organs-31 (oho31) of Drosophila encodes a protein with extensive homology to the Importin protein of Xenopus (50% identity), the related yeast SRP1 protein, and the mammalian hSRP1 and RCH1 proteins [11].
• In addition, Srp1 is also required for the execution of mitosis: we demonstrate that cells containing a conditional mutation of SRP1 arrest with a G2/M phenotype in a manner analogous to classic cdc mutants [12].

Anatomical context of SRP1

• One is allelic to srp1 which, although it was identified in an unrelated screen, was shown to encode a protein that is localized to the nuclear envelope (Yano, R., M. Oakes, M. Yamaghishi, J. A. Dodd, and M. Nomura. 1992. Mol. Cell. Biol. 12:5640-5651) [13].
• Nup2p is located on the nuclear side of the nuclear pore complex and coordinates Srp1p/importin-alpha export [10].
• All three cell wall proteins show a substantial homology with Srp1p, which also appears to be localized in the cell wall [14].
• This phenotype suggests that Srp1p is required for the normal function of microtubules and the spindle pole bodies, as well as for nuclear integrity [15].
• TIR1/SRP1 has previously been identified as a gene induced by glucose, cold shock or anaerobiosis and was believed to be a cell membrane protein but not a cell wall protein [16].

Associations of SRP1 with chemical compounds

• Biochemical and mutational analyses localized the in vitro phosphorylation site of Srp1p by CKII to serine 67 [17].
• The hypoxic SRP1/TIR1 gene encodes a stress-response cell wall mannoprotein, which is shown to be necessary for yeast growth at acidic pH in the presence of sodium dodecyl sulfate [18].
• The SRP1 gene is highly expressed in culture conditions leading to glucose repression (Marguet & Lauquin, 1986), the amount of SRP1 mRNA representing about 1 to 2% of total poly(A)+ RNA [19].
• The luciferase reporter gene under the control of the 5' flanking region of 0.7 kb was strongly induced upon activation with anti-CD3 or PHA plus PMA only in SCM-1-producer T cell lines through a cyclosporin A-sensitive mechanism [20].

Physical interactions of SRP1

• We studied the role of the nucleoporin Nup2p in the transport cycle of Srp1p [9].
• After carrying its cargo into the nucleus, the importin dimer dissociates, and Srp1p (the yeast importin alpha subunit) is recycled to the cytoplasm in a complex with Cse1p and RanGTP [21].
• Upf3p physically interacts with Srp1p (importin-alpha) [22].
• We found that Sts1p interacts directly with Srp1p in vitro and also in vivo, as judged by coimmunoprecipitation and two-hybrid analyses [23].
• We have thus identified Gcn4p as a substrate for the Srp1p/Kap95p transport complex [24].

Other interactions of SRP1

• The distant sequence similarity between Srp1p and the beta-catenin/desmoplakin family, coupled with the altered structure of the nuclear envelope in nup1 mutants, suggests that Srp1p may function in attachment of the nuclear pore complex to an underlying nuclear skeleton [13].
• We show that Nup2p effectively releases the NLS protein from importin alpha-importin and beta and strongly binds to the importin heterodimer via Srp1p [9].
• A deletion of NUP2 shows genetic interactions with mutants in SRP1 and PRP20, which encodes the Ran nucleotide exchange factor [21].
• Srp1p, the yeast nuclear localization signal-receptor, also accumulated in the nuclei of the arrested kap95 mutant cells [25].
• Moreover, NHP6A does not bind to the yeast nuclear localization signal receptor SRP1 and nuclear targeting of NHP6A does not require the function of the 14 different importins [26].

Analytical, diagnostic and therapeutic context of SRP1

• Immunoelectron microscopy confirms that these densities contain XFXFG nucleoporins. act2-1 is synthetically lethal in combination with a deletion in the XFXFG nucleoporin gene, NUP1, or a mutation in the nuclear localization sequence receptor gene, SRP1 [27].
• Using antibody against the SRP1 protein, we have found that SRP1 is mainly localized at the periphery of the nucleus, apparently more concentrated in certain regions, as suggested by a punctate pattern in immunofluorescence microscopy [28].
• Using a gel retardation assay, a protein factor that specifically interacts with a 33 bp intragenic sequence of the highly expressed and glucose-inducible SRP1 gene of Saccharomyces cerevisiae has been detected [29].
• In this study, we have used site-directed mutagenesis coupled with in vitro binding assays and in vivo analyses to investigate the intramolecular interaction of the N-terminal IBB domain and the NLS binding pocket of Saccharomyces cerevisiae importin alpha, Srp1p [30].
• Northern blot analysis of both the wild type and SRP1-disrupted strains indicated that along with SRP1 at least one more member of the SRP family was transcribed to a 0.7 kb (1 kb = 10(3) bases) polyadenylated RNA species clearly distinct from the SRP1-specific mRNA (1 kb long) [19].

References