6k7p
From Proteopedia
Crystal structure of human AFF4-THD domain
Structural highlights
Disease[AFF4_HUMAN] Note=A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a MLL-AFF4 fusion protein. Function[AFF4_HUMAN] Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.[1] [2] [3] Publication Abstract from PubMedSuper elongation complex (SEC) is a positive regulator of RNA polymerase II, which is required for HIV-1 proviral transcription. AFF1/4 is the scaffold protein that recruits other components of SEC and forms dimer depending on its THD domain (TPRL with Handle Region Dimerization Domain). Here we report the crystal structure of the human AFF4-THD at the resolution of 2.4 A. The alpha4, alpha5, and alpha6 of one AFF4-THD mediate the formation of a dimer and pack tightly against the equivalent part of the second molecule in the dimer of AFF-THD. Mutagenesis analysis revealed that single mutations of either Phe1014 or Tyr1096 of AFF4 to alanine impair the formation of the AFF4 dimer. In addition, transactivation assay also indicated that Phe1014 and Tyr1096 of AFF4 are critical to the transactivation activity of AFF4. Interestingly, the corresponding residues Phe1063 and Tyr1145 in AFF1 have an effect on the transactivation of HIV-1 provirus. However, such mutations of AFF1/4 have no effect on the interaction of AFF1/4 with other subunits of the SEC. Together, our data demonstrated that the dimerization of AFF1/4 is essential to transactivation of HIV-1 provirus. Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription.,Tang D, Chen C, Liao G, Liu J, Liao B, Huang Q, Chen Q, Zhao J, Jiang H, Duan J, Huang J, Wang K, Wang J, Zhou C, Chu W, Li W, Sun B, Li Z, Dai L, Fu X, Cheng W, Xue Y, Qi S Cell Discov. 2020 Feb 18;6:7. doi: 10.1038/s41421-020-0142-6. eCollection 2020. PMID:32128251[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Cheng, W | Duan, J | Li, S | Qi, S | Tang, D | Wang, J | Xue, Y | Aff4 | Dimerizaiton | Hiv-1 | Super elongation complex | Transcription
