C-terminal of APE enzyme involve in repairing of DNA while N-terminal in redox activation of transcription factors. Is there any report when both terminals work together in signalling or come closer to each other?
In APE1, as in some other cysteine containing proteins, the N-terminal cysteine (Cys) that acts in transcription is part of a single folded domain with the DNA binding and repair functions. APE1 forms a 4-layer structure with central pairs of beta-sheets packed on both sides by helices that is an integrated single domain structure. The reactive Cys falls on a central strand of one beta sheet where it will impact the beta sheet to helix folding interactions and likely the DNA binding site at the end of the beta strands (see S.E. Tsutakawa et al., J Biol Chem. 2013 Mar 22;288(12):8445-55). In terms of three-dimensional protein structures, a domain is defined as a folding unit, a stable folded region (that can exist independently of the rest of the amino acid sequence), or a functional unit (e.g. Zn fingers or the Rossmann fold domains that bind DNA). In essence, domains are a structural unit with more interactions within itself than with the rest of the sequence, as seen for APE1. This independence of domains is important for genetic engineering because they can often be used as building blocks and swapped with other regions to create new combined activities. Given its single domain structure, the DNA repair functions of APE1 appear structurally linked to the cysteine response functions with transcription and to some cancers. APE1 cysteine oxidation state also seems linked to its trafficking the the mitochondria, which uses most of the oxygen in the cell and is a major source of reactive oxygen species. This is an ongoing area of research, and ideas as to how to quantitatively and specifically define functional relationships among the DNA repair, trafficking, folding, and transcription activities of APE1 are valuable for going forward.
Here is the paper showing that N-terminal part of APE1 is involved in DNA glycsylase-independent nucleotide incision repair of oxidatively damaged bases (Gros et la NA 2004)
Here is the paper showing that N-terminal part of APE1 is involved in DNA glycsylase-independent nucleotide incision repair of oxidatively damaged bases (Gros et la NA 2004)
Here is the paper showing that N-terminal Lysine residues of APE1 are involved in enzymatic turnover when repairing AP sites. So there is evident link between N-terminal domain and DNA repair which can be regulated by postranslationla modifications.
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