Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription

Tang, Dan; Chen, Chunjing; Liao, Ga; Liu, Jiaming; Liao, Banghua; Huang, Qingqing; Chen, Qianqian; Zhao, Jiahui; Jiang, Hui; Duan, Jingliang; Huang, Jin; Wang, Kunjie; Wang, Jiawei; Zhou, Caijin; Chu, Wendan; Li, Wenqi; Sun, Binyong; Li, Zhonghan; Dai, Lunzhi; Fu, Xianghui; Cheng, Wei; Xue, Yuhua; Qi, Shiqian

doi:10.1038/s41421-020-0142-6

Cited by 11 publications

(13 citation statements)

References 38 publications

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“…In silico modeling of most of the identified missense variants is hampered by the lack of reliable AFFs structural information with the exception of the CHD that is important for dimerization and the ALF that contains the degron and the ELL-binding domains (ELLbow, see below) 44,45 . The p.(Gln1020Arg), p.(Val1036Ile), p.(Arg1186Gln) and p.(Gly1215Val) variants fall within the CHD ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

Variant-specific pathophysiological mechanisms ofAFF3differently influence transcriptome profiles

Bassani,

Chrast,

Ambrosini

et al. 2024

Preprint

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Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3 . We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

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Section: Resultsmentioning

confidence: 99%

Variant-specific pathophysiological mechanisms ofAFF3differently influence transcriptome profiles

Bassani,

Chrast,

Ambrosini

et al. 2024

Preprint

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“…Although the crystal structure of AF4-AFF4 heterodimer is not available, that of the homodimer of AFF4 CHD domain has been determined (PDB: 6R80) [ 168 , 207 , 208 ]. Biochemical including mutagenesis studies revealed that the interface between AF4 and AFF4 heterodimer overlap with that of AFF4 homodimer, thanks to a high degree of homology between the two CHD domains.…”

Section: Ppis Involving Mll1 Fusion Proteinsmentioning

confidence: 99%

Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

Song

2021

J Hematol Oncol

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Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5–10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains of MLL1 fused with one of > 70 fusion partners, among which transcription cofactors AF4, AF9 and its paralog ENL, and ELL are the most frequent. Wild-type (WT)- and onco-MLL1 involve numerous protein–protein interactions (PPI), which play critical roles in regulating gene expression in normal physiology and leukemia. Moreover, WT-MLL1 has been found to be essential for MLL1-rearranged (MLL1-r) leukemia. Rigorous studies of such PPIs have been performed and much progress has been achieved in understanding their structures, structure–function relationships and the mechanisms for activating gene transcription as well as leukemic transformation. Inhibition of several critical PPIs by peptides, peptidomimetic or small-molecule compounds has been explored as a therapeutic approach for MLL1-r leukemia. This review summarizes the biological functions, biochemistry, structure and inhibition of the critical PPIs involving MLL1 and its fusion partner proteins. In addition, challenges and perspectives of drug discovery targeting these PPIs for the treatment of MLL1-r leukemia are discussed.

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“…[135][136][137][138][139] Although antiretroviral therapies (ARTs) have been used as a major treatment for AIDS, HIV-1 remains incurable due to its mutation, latency, and destruction of T cells. [140][141][142][143][144][145][146][147][148][149][150] Because HIV remains one of the most significant public health problems worldwide, elucidating each step of the HIV life cycle is necessary to develop more effective therapies.…”

Section: Tmem16f and Hiv Infectionmentioning

confidence: 99%

Scramblases and virus infection

et al. 2022

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The asymmetric distribution of lipids, maintained by flippases/floppases and scramblases, plays a pivotal role in various physiologic processes. Scramblases are proteins that move phospholipids between the leaflets of the lipid bilayer of the cellular membrane in an energy-independent manner. Recent studies have indicated that viral infection is closely related to cellular lipid distribution. The level and distribution of phosphatidylserine (PtdSer) in cells have been demonstrated to be critical regulators of viral infections. Previous studies have supported that the infection of human immunodeficiency virus (HIV), Zika virus, Ebola virus (EBOV), influenza virus, and dengue fever virus require the externalization of phospholipids mediated by scramblases, which are also involved in the pathogenicity of the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we review the relationship of scramblases with viruses and the potential viral effector proteins that might utilize host scramblases.

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Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription

Cited by 11 publications

References 38 publications

Variant-specific pathophysiological mechanisms ofAFF3differently influence transcriptome profiles

Variant-specific pathophysiological mechanisms ofAFF3differently influence transcriptome profiles

Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

Scramblases and virus infection

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