| Structural highlights
Disease
[SFPQ_HUMAN] Translocation renal cell carcinoma. A chromosomal aberration involving SFPQ may be a cause of papillary renal cell carcinoma (PRCC). Translocation t(X;1)(p11.2;p34) with TFE3.
Function
[SFPQ_HUMAN] DNA- and RNA binding protein, involved in several nuclear processes. Essential pre-mRNA splicing factor required early in spliceosome formation and for splicing catalytic step II, probably as a heteromer with NONO. Binds to pre-mRNA in spliceosome C complex, and specifically binds to intronic polypyrimidine tracts. Involved in regulation of signal-induced alternative splicing. During splicing of PTPRC/CD45, a phosphorylated form is sequestered by THRAP3 from the pre-mRNA in resting T-cells; T-cell activation and subsequent reduced phosphorylation is proposed to lead to release from THRAP3 allowing binding to pre-mRNA splicing regulatotry elements which represses exon inclusion. Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b. May be involved in a pre-mRNA coupled splicing and polyadenylation process as component of a snRNP-free complex with SNRPA/U1A. The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs. SFPQ may be involved in homologous DNA pairing; in vitro, promotes the invasion of ssDNA between a duplex DNA and produces a D-loop formation. The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1; in vitro, stimulates dissociation of TOP1 from DNA after cleavage and enhances its jumping between separate DNA helices. The SFPQ-NONO heteromer may be involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends; in vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex. SFPQ is involved in transcriptional regulation. Transcriptional repression is mediated by an interaction of SFPQ with SIN3A and subsequent recruitment of histone deacetylases (HDACs). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity. SFPQ isoform Long binds to the DNA binding domains (DBD) of nuclear hormone receptors, like RXRA and probably THRA, and acts as transcriptional corepressor in absence of hormone ligands. Binds the DNA sequence 5'-CTGAGTC-3' in the insulin-like growth factor response element (IGFRE) and inhibits IGF-I-stimulated transcriptional activity. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex through histone deacetylation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [PSPC1_HUMAN] Regulates, cooperatively with NONO and SFPQ, androgen receptor-mediated gene transcription activity in Sertoli cell line (By similarity). Binds to poly(A), poly(G) and poly(U) RNA homopolymers (By similarity). Together with NONO, required for the formation of nuclear paraspeckles.[11]
Publication Abstract from PubMed
Members of the Drosophila Behavior Human Splicing (DBHS) protein family are nuclear proteins implicated in many layers of nuclear functions, including RNA biogenesis as well as DNA repair. Definitive of the DBHS protein family, the conserved DBHS domain provides a dimerization platform that is critical for the structural integrity and function of these proteins. The three human DBHS proteins - splicing factor proline- and glutamine-rich (SFPQ), paraspeckle component 1 (PSPC1), and non-POU domain-containing octamer binding protein (NONO) - form either homo- or heterodimers; however, the relative affinity and mechanistic details of preferential heterodimerization are yet to be deciphered. Here we report the crystal structure of a SFPQ/PSPC1 heterodimer to 2.3 A resolution and analyzed the subtle structural differences between the SFPQ/PSPC1 heterodimer and the previously characterized SFPQ homodimer. Analytical ultracentrifugation to estimate the dimerization equilibrium of the SFPQ-containing dimers revealed that the SFPQ-containing dimers dissociate at low micromolar concentrations and that the heterodimers have higher affinities than the homodimer. Moreover, we observed that the apparent dissociation constant for the SFPQ/PSPC1 heterodimer was over six-fold lower than that of the SPFQ/NONO heterodimer. We propose that these differences in dimerization affinity may represent a potential mechanism by which PSPC1 at a lower relative cellular abundance can outcompete NONO to heterodimerize with SFPQ.
Crystal structure of a SFPQ/PSPC1 heterodimer provides insights into preferential heterodimerization of human DBHS family proteins.,Huang J, Casas Garcia GP, Perugini MA, Fox A, Bond C, Lee M J Biol Chem. 2018 Mar 12. pii: RA117.001451. doi: 10.1074/jbc.RA117.001451. PMID:29530979[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Urban RJ, Bodenburg Y, Kurosky A, Wood TG, Gasic S. Polypyrimidine tract-binding protein-associated splicing factor is a negative regulator of transcriptional activity of the porcine p450scc insulin-like growth factor response element. Mol Endocrinol. 2000 Jun;14(6):774-82. PMID:10847580
- ↑ Straub T, Knudsen BR, Boege F. PSF/p54(nrb) stimulates "jumping" of DNA topoisomerase I between separate DNA helices. Biochemistry. 2000 Jun 27;39(25):7552-8. PMID:10858305
- ↑ Akhmedov AT, Lopez BS. Human 100-kDa homologous DNA-pairing protein is the splicing factor PSF and promotes DNA strand invasion. Nucleic Acids Res. 2000 Aug 15;28(16):3022-30. PMID:10931916
- ↑ Mathur M, Tucker PW, Samuels HH. PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors. Mol Cell Biol. 2001 Apr;21(7):2298-311. PMID:11259580 doi:http://dx.doi.org/10.1128/MCB.21.7.2298-2311.2001
- ↑ Zhang Z, Carmichael GG. The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell. 2001 Aug 24;106(4):465-75. PMID:11525732
- ↑ Sewer MB, Nguyen VQ, Huang CJ, Tucker PW, Kagawa N, Waterman MR. Transcriptional activation of human CYP17 in H295R adrenocortical cells depends on complex formation among p54(nrb)/NonO, protein-associated splicing factor, and SF-1, a complex that also participates in repression of transcription. Endocrinology. 2002 Apr;143(4):1280-90. PMID:11897684 doi:http://dx.doi.org/10.1210/endo.143.4.8748
- ↑ Bladen CL, Udayakumar D, Takeda Y, Dynan WS. Identification of the polypyrimidine tract binding protein-associated splicing factor.p54(nrb) complex as a candidate DNA double-strand break rejoining factor. J Biol Chem. 2005 Feb 18;280(7):5205-10. Epub 2004 Dec 7. PMID:15590677 doi:http://dx.doi.org/10.1074/jbc.M412758200
- ↑ Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell. 2010 Oct 8;40(1):126-37. doi: 10.1016/j.molcel.2010.09.013. PMID:20932480 doi:10.1016/j.molcel.2010.09.013
- ↑ Gozani O, Patton JG, Reed R. A novel set of spliceosome-associated proteins and the essential splicing factor PSF bind stably to pre-mRNA prior to catalytic step II of the splicing reaction. EMBO J. 1994 Jul 15;13(14):3356-67. PMID:8045264
- ↑ Patton JG, Porro EB, Galceran J, Tempst P, Nadal-Ginard B. Cloning and characterization of PSF, a novel pre-mRNA splicing factor. Genes Dev. 1993 Mar;7(3):393-406. PMID:8449401
- ↑ Passon DM, Lee M, Rackham O, Stanley WA, Sadowska A, Filipovska A, Fox AH, Bond CS. Structure of the heterodimer of human NONO and paraspeckle protein component 1 and analysis of its role in subnuclear body formation. Proc Natl Acad Sci U S A. 2012 Mar 13. PMID:22416126 doi:10.1073/pnas.1120792109
- ↑ Huang J, Casas Garcia GP, Perugini MA, Fox A, Bond C, Lee M. Crystal structure of a SFPQ/PSPC1 heterodimer provides insights into preferential heterodimerization of human DBHS family proteins. J Biol Chem. 2018 Mar 12. pii: RA117.001451. doi: 10.1074/jbc.RA117.001451. PMID:29530979 doi:http://dx.doi.org/10.1074/jbc.RA117.001451
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