Disease relevance of SRPR

• By using hybrids containing various fragments of chromosome 11q, SRPR has been mapped to a chromosomal region flanked by the 11q23 and 11q24 breakpoints associated with the constitutional and neuroepithelioma (11;22) translocations, respectively [1].
• Signal recognition particle receptor (SRPR) is downregulated in a rat model of cyclosporin A-induced gingival overgrowth [2].
• We developed a novel promoter system, designated SR alpha, which is composed of the simian virus 40 (SV40) early promoter and the R segment and part of the U5 sequence (R-U5') of the long terminal repeat of human T-cell leukemia virus type 1 [3].
• We report the effect of glucose on the expression of the gene encoding the pyruvate dehydrogenase (E1) alpha subunit (E1alpha) in human hepatoma (HepG2) cells [4].
• Whereas both the low-risk (1 and 6b) and the high-risk (16, 18, and 33) HPVs were transactivating for the adenovirus E2 promoter, only the high-risk HPVs were capable of focal transformation as assayed by an efficient method using the SR alpha-promoter and in conjunction with the HPV 16 E6 gene [5].

High impact information on SRPR

• Patients with the disorder have no HLA-DR, DQ, or DP antigens or mRNAs in their peripheral-blood lymphocytes [6].
• Lymphoblastoid B-cell lines from the patients contained no mRNA for HLA-DR, DQ, and DP alpha and beta polypeptides, but did express mRNA for the HLA-associated invariant chain, which is normally coregulated with HLA Class II antigens [6].
• Alkylation of the 68/72 kd protein of SRP yields a particle that arrests elongation but fails to promote translocation and no longer interacts with SRP receptor [7].
• In eukaryotes, proteins are inserted into the endoplasmic reticulum using the signal recognition particle (SRP) and the SRP receptor, as well as the integral membrane Sec61 trimeric complex (composed of alpha, beta and gamma subunits) [8].
• Targeting is regulated by three GTPases, the 54K subunit of SRP (SRP54), and the alpha- and beta-subunits of the SRP receptor [9].

Chemical compound and disease context of SRPR

• A methionine at position 11 of the DP alpha molecule (Met-11) and DPA1*0301 were associated with schistosomiasis when compared with controls (phenotypic gene frequencies = 0.791 versus 0.583 and 0.555 versus 0.375, respectively) [10].

Biological context of SRPR

• The signal recognition particle (SRP) functions in conjunction with the SRP receptor to target nascent ectoplasmic proteins to the protein translocation machinery of the endoplasmic reticulum membrane [11].
• Molecular map of the human HLA-SB (HLA-DP) region and sequence of an SB alpha (DP alpha) pseudogene [12].
• A strong pause site at nucleotide 507 of the mRNA open reading frame corresponded with the shortest nascent SR alpha polypeptide able to assemble on membranes [13].
• To examine the biogenesis of the SRP receptor we have developed a cell-free assay system that reconstitutes SR alpha membrane assembly and permits both anchoring and functional properties to be assayed independently [14].
• Contrary to earlier preliminary findings with a limited number of enzymes, the RFLP appears to be quite extensive both with the DP beta (14 different DNA markers defined by individual fragments or clusters thereof) and the DP alpha (8 markers) probes, especially when enzymes recognizing only four base pairs were used [15].

Anatomical context of SRPR

• A polymerase chain reaction (PCR)-based assay has been designed that detects the presence of the human signal recognition particle receptor (SRPR) gene in inter-species somatic cell hybrids [1].
• Docking protein (DP, or SRP receptor) is an essential component of the cellular machinery that mediates the targeting of nascent secretory and membrane proteins to the rough endoplasmic reticulum (ER) [16].
• Signal recognition particle (SRP) and SRP receptor are known to be essential components of the cellular machinery that targets nascent secretory proteins to the endoplasmic reticulum (ER) membrane [17].
• When a signal sequence emerges from the ribosome, SRP interacts with it and targets the resulting complex to the ER membrane by binding to the SRP receptor [9].
• This was combined with spotty expression of HBsAg (cytoplasm and liver cell membrane) and with Dane particles (DP) in blood [18].

Associations of SRPR with chemical compounds

• Furthermore, we found that the arrest-releasing activity of the SRP receptor can be inactivated by alkylation of K-RM with N-ethylmaleimide [19].
• Mutational analysis of the E1alpha promoter region has identified two regions, from -78 to -73 bp (CCCCTG) and from -8 to -3 bp (GCGGTG), that are responsible for the effect of glucose on promoter activity; the former exhibits a larger effect [4].
• Total pyruvate dehydrogenase complex activity as well as the levels of protein and mRNA of the E1alpha subunit were significantly increased in HepG2 cells cultured in medium containing 16.7 mM glucose compared with 1.0 mM glucose for a period of 4 weeks [4].
• Tethered hydroxyl radical probing data reveal that specific positioning of the RNA tetraloop within the SRP-receptor complex is required to stimulate GTPase activity to a level sufficient to support cell growth [20].
• Finally, we report that treatment of LAN-5 cells with cycloheximide did not alter the rate of transcription of the HLA-DP alpha gene, suggesting that no protein factor(s) is/are needed to maintain DP alpha gene expression [21].

Physical interactions of SRPR

• Biochemical studies show that whereas Tal 1B5 reacts with DR alpha-chains, Tal 3C3 predominantly defines DP alpha-chain subunits and a high molecular weight (200-250 kD) actin binding protein known as filamin [22].
• All three proteins bind GTP specifically, and the SR alpha/SR beta complex stimulates both GTP binding to and GTP hydrolysis by SRP54 [23].

Regulatory relationships of SRPR

• We also describe the stable transfection of Chinese hamster ovary cells with a plasmid containing the IDE cDNA under the transcriptional control of the SR alpha promoter [24].
• We constructed an expression vector containing sense- or antisense-oriented human TSC-22 cDNA under the transcriptional control of the SR alpha promoter [25].

Other interactions of SRPR

• SRP68 also accumulated in the ER, consistent with its affinity for the ER-bound SRP receptor [26].
• The conservation of this sequence, in combination with the results of earlier genetic and biochemical studies of the SRP cycle, leads us to hypothesize that a component of the Srp68/72p heterodimer serves as the GDS for both Srp54p and SR alpha [27].
• An expression plasmid containing an insert of CYP2E1 cDNA and SR alpha promoter was constructed and transfected into the cultured cell line CR-119 which had previously been established by introducing a cDNA coding for NADPH-cytochrome P450 reductase [28].
• Nuclear run-on assays and promoter analysis indicate that the glucose-induced increases in the levels of E1alpha mRNA in HepG2 cells are due to increased transcription of the human E1alpha (PDHA1) gene [4].
• The genes for HLA-DR beta, DQ alpha and DP alpha were present in the HAJ genome as detected with polymerase chain reaction (PCR) using locus-specific primers amplifying a second exon [29].

Analytical, diagnostic and therapeutic context of SRPR

• When SRP receptor was purified by SRP-Sepharose affinity chromatography, we observed the co-purification of two other ER membrane proteins [17].
• A 60,000-dalton protein fragment (Meyer, D. I., and B. Dobberstein, 1980, J. Cell Biol., 87:503-508) that had been shown previously to reconstitute the translocation activity of protease-digested membranes, was shown here by peptide mapping and immunological criteria to be derived from the SRP receptor [30].
• Thus, Southern blotting seems feasible for typing for most DP determinants by specific fragments or subtraction between the various more broadly reactive DNA markers, and the RFLP provides further information on the DP subregion in addition to that provided by primed lymphocyte typing [15].
• ELISA typing results, based on two polymorphic DP antibodies DP11.1 and ILR1, were compared with PLT-defined and RFLP-defined types [31].
• To confirm and extend the immunological data to all the class-II molecules, we performed Northern blot analysis, observing that DP alpha mRNA was induced in a dose- and time-dependent manner [21].

References