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  • labetalol hydrochloride australia The AT hook motif is

    2024-06-12

    The AT-hook motif is highly conserved in evolution from bacteria to humans and is found in one or more copies in a large number of other, non-HMGA, proteins, many of which are transcription factors or are involved in chromatin remodeling [8]. For example, AT-hook peptide motifs are essential components of the multiprotein, ATP-dependent chromatin remodeling complexes or “machines” found in yeast, slime mold, insect, plant and mammalian cells. Specifically, AT-hooks are found in the Rsc-1 and Rsc-2 proteins of the Saccharomyces RSC chromatin remodeling complex [28]; the multifunctional CbfA remodeling protein of Dictyostelium[94]; the largest protein subunit of the NURF chromatin remodeling complex of Drosophila[170]; the SPLAYED protein of Arabidopsis[155]; the APRIN chromatin remodeling protein of mammals [96]; the human MRN remodeling complex involved in double strand break repair [167]; and both the BRM/SNF2α and the BRG-1/SNF2β ATPase proteins of the human SWI/SNF-like complexes [21,150]. Furthermore, and most importantly, site-specific mutagenesis studies have demonstrated that when the AT-hook peptide motifs of the human BRG1 protein are deleted or mutated, both the nucleosome-binding and the ATP-dependent chromatin remodeling activities of the SWI/SNF complex were destroyed or greatly attenuated [21]. Together these findings suggest that most, if not all, of the major ATP-dependent chromatin remodeling complexes in eukaryotic labetalol hydrochloride australia contain proteins with functional AT-hooks that are involved in binding to nucleosomes in a manner similar to that of the HMGA proteins themselves. It thus seems likely that in vivo there is an intimate, and perhaps reciprocal, interaction between the AT-hook motifs of the HMGA proteins and those of the ATP-dependent chromatin remodeling machines in nuclear processes that require alterations in nucleosome structure. There are numerous cases in which HMGA proteins have been linked to localized changes in chromatin structure that are coupled with concomitant alterations in the phenotypic characteristics of cells. Perhaps the best documented example involves the complex molecular and phenotypic cellular changes that follow virus infection. Healthy cells do not normally produce type I interferons (IFN-α and IFN-β), secreted proteins of the innate immune response that interfere with viral replication and help block the spread of viruses to uninfected cells. Soon after viral infection, however, cells undergo a marked phenotypic change and start producing copious quantities of IFN-β followed about 24 h later by a rapid postproduction turnoff. Double-stranded RNA produced during the viral life cycle induces assembly of an HMGA-containing enhanceosome on the promoter of the IFN-β gene and the initiation of mRNA transcription [157]. The intricate mechanics and multiple steps involved in the assembly/disassembly of the IFN-β enhanceosome during interferon turn on/off have been described in detail [5,99]. HMGA1 is a key player in coordinating enhanceosome assembly/disassembly and initiates the transcription activation process by binding to, and straightening, a short run of A/T-residues in naked DNA located between two well-positioned nucleosomes on the IFN-β promoter [5,47,157,172,173]. The bound HMGA1 then assists in recruiting a number of transcription factors (IRF-1, p50, p65 and ATF-2/c-Jun) to an array of binding site on the naked DNA and coordinates the formation of the enhanceosome [172]. The stereospecific surface of the enhanceosome then recruits the GCN5 histone acetyltransferase (HAT) complex which acetylates histones on both of the adjacent nucleosomes but without altering their positions. GCN5 also acetylates a specific residue (K71) in the HMGA1 protein which strengthens the protein–protein interactions within the enhanceosome and is crucial for maintaining its stability during the transcription process [99,100]. Next, an SWI/SNF nucleosome remodeling complex and another HAT enzyme (CBP) are recruited to the enhanceosome. As a result of SWI/SNF remodeling activity, one of the two positioned nucleosomes moves or “slides” 37 bp downstream on the promoter, unmasking the TATA box and allowing TBP/RNA polymerase II holoenzyme recruitment and initiation of robust mRNA transcription [92,93]. Continuous acetylation of K71 on HMGA1 is required for transcription since deacetylation of this residue followed by acetylation of an adjacent lysine (K65) on the proteins by CBP leads to enhanceosome disruption and the termination of transcription [102–104]. Thus, dynamic acetylation/deacetylation of specific residues on the HMGA1 protein has been proposed to act as a regulatory “switch” controlling the stabilization/disruption of the IFN-β enhanceosome. A potential caveat to this idea comes, however, from recent structural studies which have provided a complete atomic model of the protein–DNA interface of the IFN-β enhanceosome (reviewed in [115]). These studies demonstrate that the fully assembled enhanceosome cannot accommodate the HMGA1 protein since the minor grooves of all of its potential binding sites are either sterically blocked by other proteins or are too narrow to accommodate binding of the protein's AT-hooks. Therefore HMGA1 is unlikely to be a part of the final enhanceosome assembly. A possible explanation for this apparent discrepancy is that HMGA1 acts as a DNA molecular chaperone during enhanceosome assembly and, following its formation, dissociates from the final complex. Such a “hit-and-run” mode of transcriptional regulation has been proposed for the HMGB family of proteins [6], as will be discussed below.