User:Juliet Obi/Sandbox 1
From Proteopedia
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Bromodomain Adjacent to Zinc Finger domain 1A
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Overview
Bromodomain adjacent to zinc finger 1A (BAZ1A) is a protein in humans encoded by the BAZ1A gene. The protein encoded by the BAZ1A gene contains the accessory subunit of the ATP-dependent chromatin assembly factor (ACF), which is a member of the imitation switch (ISWI) family of chromatin remodeling complexes including BAZ1B, BAZ2A and BAZ2B. BAZ1A structure contains a plant homeodomain (PHD) zinc finger at the N-terminus, a bromodomain at the C-terminus, a WAC motif and a LH (leucine-rich helical domain) motif [1]. BAZ1A is also known as ACF1, WALp1, hACF1 or WCRF180 [2].
BAZ1A function
BAZ1A encodes the chromatin-remodeling factor ACF1, which is a member of the ISWI chromatin remodeling complexes including the ATP-dependent chromatin assembly factor ACF, and the chromatin accessibility complex, CHRAC. BAZ1A (ACF1) has been implicated in a number of functions including chromatin remodeling, assembly and DNA repair. Together with the ISWI subunit, it has been shown to assemble regularly spaced nucleosome arrays in an ATP-dependent manner [3]. BAZ1A functions in certain DNA repair pathways including nucleotide excision repair (NER), non-homologous end-joining (NHEJ) and homologous recombination (HR), through interaction with a catalytic ATPase subunit, SMARCA5 [4]. BAZ1A has been shown to have a regulatory function in the transcriptional suppression of vitamin D3 receptor-regulated genes [5], and in the transcriptional regulation of stress-induced depressive-like behaviors [6]. A recent study with an identified variant in BAZ1A found that this affects the transcriptional regulatory function of ACF1, thus affecting the expression of genes crucial in vitamin D metabolism, the Wnt signalling pathway, and in proper synaptic function, highlighting the important role BAZ1A has in nervous system development and function [7].
Structural features, evolution and related structures
BAZ1A bromodomain histone-ligand recognition
BAZ1A bromodomain as well as BAZ1B a similar bromodomain family member, both have a conserved asparagine "anchor" residue which in functional bromodomains, hydrogen bonds with the carbonyl group of a bound acetyl-lysine ligand and it is crucial for the interaction. This suggests that BAZ1A and BAZ1B could potentially bind an acety-lysine ligand [8]. Also, BAZ1B has an hydrophobic valine "gatekeeper" residue which is found in the binding pockets of several acetyl-lysine binding bromodomains [9]. Surprisingly, the BAZ1A bromodomain gatekeeper was found to be a non-canonical glutamic acid residue which was found to be compatible with the bromodomain fold through the solving of the crystal structure of BAZ1A bromodomain. The glutamic acid residue introduces a negative charge on the side of the supposed binding pocket of BAZ1A which reduces its affinity for acetylated histone ligands [10].
BAZ1A-PHD binding to DNA
The PHD finger of bromodomains serves as an epigenetic reader by recognizing the N-terminal histone H3 tail when it is methylated [11]. The function of BAZ1A-PHD, N-terminal to its bromodomain, is however unknown [10]. This can be attributed to the fact that BAZ1A-PHD lacks the "aromatic cage" as well as other key residues crucial for the recognition of trimethylated lysine [12]. BAZ1A-PHD also lacks acidic residues which particularly recognize unmethylated histone H3 lysine 4 (H3K4) peptides [13]. These information show proof that the PHD finger of BAZ1A might interact with DNA through its other biochemical properties other than the canonical residues which are absent [10].
The PHD of BAZ1A is structurally similar to its paralog, BAZ1B-PHD and the dual-zinc binding motif characteristic of their PHD fold have been found to be structurally conserved. BAZ1A-PHD is 54% identical and 73% similar to BAZ1B-PHD [10]. However, BAZ1A-PHD has been found to contain a positively charged feature possibly due to the closely spaced lysine residues on the K1181 and K1183 positions. The positive charge could be involved in binding a negatively charged partner such as DNA and studies have shown binding affinities tests to confirm this [10]. Although the N-terminal WAC motif of BAZ1A has been shown to bind nucleosomes by a linker DNA in the regulation of the BAZ1A-SMARCA5 complex (ACF complex) [14], the BAZ1A PHD-DNA interaction has been shown not to be needed for this process [10].
Ligand-interaction domain
BAZ1A has 4 polypeptide chains and a unique ligand EPE, on chains B and D.
Medical importance
BAZ1A in complex with SMARCA5 has been implicated in different DNA repair mechanisms [15]. A decrease in BAZ1A expression impairs recovery from DNA damage in human cells [16] [17]. Mutations in the PHD of BAZ1A can disrupt DNA binding and cause transcriptional deregulation before or after DNA damage. The specific target(s) of BAZ1A to DNA damage sites remain unknown, although there is an hypothesis that the DNA binding surface of BAZ1A-PHD is required for disengaging BAZ1A from chromatin after a DNA repair process but it needs to be tested [10].
