| Structural highlights
Function
[HTSF1_HUMAN] Functions as a general transcription factor playing a role in the process of transcriptional elongation. May mediate the reciprocal stimulatory effect of splicing on transcriptional elongation. In case of infection by HIV-1, it is up-regulated by the HIV-1 proteins NEF and gp120, acts as a cofactor required for the Tat-enhanced transcription of the virus.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Stable recognition of the intron branchpoint by the U2 snRNP to form the pre-spliceosome is the first ATP-dependent step of splicing. Genetic and biochemical data from yeast indicate that Cus2 aids U2 snRNA folding into the stem IIa conformation prior to pre-spliceosome formation. Cus2 must then be removed by an ATP-dependent function of Prp5 before assembly can progress. However, the location from which Cus2 is displaced and the nature of its binding to the U2 snRNP are unknown. Here, we show that Cus2 contains a conserved UHM (U2AF homology motif) that binds Hsh155, the yeast homolog of human SF3b1, through a conserved ULM (U2AF ligand motif). Mutations in either motif block binding and allow pre-spliceosome formation without ATP. A 2.0 A resolution structure of the Hsh155 ULM in complex with the UHM of Tat-SF1, the human homolog of Cus2, and complementary binding assays show that the interaction is highly similar between yeast and humans. Furthermore, we show that Tat-SF1 can replace Cus2 function by enforcing ATP-dependence of pre-spliceosome formation in yeast extracts. Cus2 is removed before pre-spliceosome formation, and both Cus2 and its Hsh155 ULM binding site are absent from available cryo-EM structure models. However, our data are consistent with the apparent location of the disordered Hsh155 ULM between the U2 stem-loop IIa and the HEAT-repeats of Hsh155 that interact with Prp5. We propose a model in which Prp5 uses ATP to remove Cus2 from Hsh155 such that extended base pairing between U2 snRNA and the intron branchpoint can occur.
Cus2 enforces the first ATP-dependent step of splicing by binding to yeast SF3b1 through a UHM-ULM interaction.,Talkish J, Igel H, Hunter O, Horner SW, Jeffery NN, Leach JR, Jenkins JL, Kielkopf CL, Ares M Jr RNA. 2019 May 20. pii: rna.070649.119. doi: 10.1261/rna.070649.119. PMID:31110137[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Parada CA, Roeder RG. A novel RNA polymerase II-containing complex potentiates Tat-enhanced HIV-1 transcription. EMBO J. 1999 Jul 1;18(13):3688-701. PMID:10393184 doi:10.1093/emboj/18.13.3688
- ↑ Kim JB, Yamaguchi Y, Wada T, Handa H, Sharp PA. Tat-SF1 protein associates with RAP30 and human SPT5 proteins. Mol Cell Biol. 1999 Sep;19(9):5960-8. PMID:10454543
- ↑ Fong YW, Zhou Q. Relief of two built-In autoinhibitory mechanisms in P-TEFb is required for assembly of a multicomponent transcription elongation complex at the human immunodeficiency virus type 1 promoter. Mol Cell Biol. 2000 Aug;20(16):5897-907. PMID:10913173
- ↑ Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity. 2001 Jun;14(6):763-77. PMID:11420046
- ↑ Fong YW, Zhou Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature. 2001 Dec 20-27;414(6866):929-33. PMID:11780068 doi:http://dx.doi.org/10.1038/414929a
- ↑ Misse D, Gajardo J, Oblet C, Religa A, Riquet N, Mathieu D, Yssel H, Veas F. Soluble HIV-1 gp120 enhances HIV-1 replication in non-dividing CD4+ T cells, mediated via cell signaling and Tat cofactor overexpression. AIDS. 2005 Jun 10;19(9):897-905. PMID:15905670
- ↑ Zhou Q, Sharp PA. Tat-SF1: cofactor for stimulation of transcriptional elongation by HIV-1 Tat. Science. 1996 Oct 25;274(5287):605-10. PMID:8849451
- ↑ Li XY, Green MR. The HIV-1 Tat cellular coactivator Tat-SF1 is a general transcription elongation factor. Genes Dev. 1998 Oct 1;12(19):2992-6. PMID:9765201
- ↑ Talkish J, Igel H, Hunter O, Horner SW, Jeffery NN, Leach JR, Jenkins JL, Kielkopf CL, Ares M Jr. Cus2 enforces the first ATP-dependent step of splicing by binding to yeast SF3b1 through a UHM-ULM interaction. RNA. 2019 May 20. pii: rna.070649.119. doi: 10.1261/rna.070649.119. PMID:31110137 doi:http://dx.doi.org/10.1261/rna.070649.119
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