6n3d
Structure of HIV Tat-specific factor 1 U2AF Homology Motif (APO-State)
Structural highlights
FunctionHTSF1_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 PubMedThe transcription elongation and pre-mRNA splicing factor Tat-SF1 associates with the U2 small nuclear ribonucleoprotein (snRNP) of the spliceosome. However, the direct binding partner and underlying interactions mediating the Tat-SF1-U2 snRNP association remain unknown. Here, we identified SF3b1 as a Tat-SF1-interacting subunit of the U2 snRNP. Our 1.1 A resolution crystal structure revealed that Tat-SF1 contains a U2AF homology motif (UHM) protein-protein interaction module. We demonstrated that Tat-SF1 preferentially and directly binds the SF3b1 subunit compared to other U2AF ligand motif (ULM)-containing splicing factors, and further established that SF3b1 association depends on the integrity of the Tat-SF1 UHM. We next compared the Tat-SF1 binding affinities for each of the five known SF3b1 ULMs and then determined the structures of representative high- and low-affinity SF3b1 ULM complexes with the Tat-SF1 UHM at 1.9 A and 2.1 A resolutions, respectively. These structures revealed a canonical UHM-ULM interface, comprising a Tat-SF1 binding pocket for a ULM tryptophan (SF3b1 W338) and electrostatic interactions with a basic ULM tail. Importantly, we found that SF3b1 regulates Tat-SF1 levels and that these two factors influence expression of overlapping representative transcripts, consistent with a functional partnership of Tat-SF1 and SF3b1. Altogether, these results define a new molecular interface of the Tat-SF1-U2 snRNP complex for gene regulation. The pre-mRNA splicing and transcription factor Tat-SF1 is a functional partner of the spliceosome SF3b1 subunit via a U2AF homology motif interface.,Loerch S, Leach JR, Horner SW, Maji D, Jenkins JL, Pulvino M, Kielkopf CL J Biol Chem. 2018 Dec 19. pii: RA118.006764. doi: 10.1074/jbc.RA118.006764. PMID:30567737[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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