6l94 | pdb_00006l94
The structure of the dioxygenase ABH1 from mouse
Structural highlights
FunctionALKB1_MOUSE Dioxygenase that acts as on nucleic acids, such as DNA and tRNA (PubMed:27027282, PubMed:27745969). Requires molecular oxygen, alpha-ketoglutarate and iron (PubMed:27027282). A number of activities have been described for this dioxygenase, but recent results suggest that it mainly acts as on tRNAs and mediates their demethylation or oxidation depending on the context and subcellular compartment (By similarity). Mainly acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs, with a preference for N(1)-methyladenine at position 58 (m1A58) present on a stem loop structure of tRNAs (PubMed:27745969). Acts as a regulator of translation initiation and elongation in response to glucose deprivation: regulates both translation initiation, by mediating demethylation of tRNA(Met), and translation elongation, N(1)-methyladenine-containing tRNAs being preferentially recruited to polysomes to promote translation elongation (By similarity). In mitochondrion, specifically interacts with mt-tRNA(Met) and mediates oxidation of mt-tRNA(Met) methylated at cytosine(34) to form 5-formylcytosine (f(5)c) at this position (By similarity). mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation (By similarity). Specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA (PubMed:27027282). N(6)-methyladenosine (m6A) DNA is present at some L1 elements in embryonic stem cells and probably promotes their silencing (PubMed:27027282). Demethylates mRNAs containing N(3)-methylcytidine modification (By similarity). Also able to repair alkylated single-stranded DNA by oxidative demethylation, but with low activity (By similarity). Also has DNA lyase activity and introduces double-stranded breaks at abasic sites: cleaves both single-stranded DNA and double-stranded DNA at abasic sites, with the greatest activity towards double-stranded DNA with two abasic sites (By similarity). DNA lyase activity does not require alpha-ketboglutarate and iron and leads to the formation of an irreversible covalent protein-DNA adduct with the 5' DNA product (By similarity). DNA lyase activity is not required during base excision repair and class switch recombination of the immunoglobulin heavy chain during B lymphocyte activation (PubMed:23825659). May play a role in placental trophoblast lineage differentiation (PubMed:18163532).[UniProtKB:Q13686][1] [2] [3] [4] Publication Abstract from PubMedLung cancer has surpassed breast cancer as the leading cause of cancer death in females in developed countries and the leading cause of cancer death in males. Despite extensive research on lung cancer, the pathogenesis of lung cancer is not fully understood. ALKBH1 is a 2-oxoglutarate and Fe (II)-dependent dioxygenase responsible for the demethylation of 6-methyladenine (m6A) in RNA and is essential to multiple cellular processes in human. Numerous recent studies suggest that ALKBH1 plays a role in tumorigenesis and tumor progression, but the role of ALKBH1 in lung cancer is largely unknown. In this study, we demonstrated that the expression levels of ALKBH1 in lung cancer tissues and cells were up regulated. The invasion and migration abilities of lung cancer cells were significantly suppressed in vitro upon the silencing of ALKBH1 while they were significantly promoted upon its overexpression. We next characterized the enzyme biochemically by analyzing the contribution of essential residues Y184, H231, D233, H287, R338, and R344 to its m6A demethylation activity. Lastly, our 3.1-A crystal structure of mouse ALKBH1 revealed that the N-terminal domain of the protein forms close contacted with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. In summary, our combined cellular, biochemical, and structural results provide insight into the potential ALKBH1-based drug design for cancer therapies. ALKBH1 promotes lung cancer by regulating m6A RNA demethylation.,Li H, Zhang Y, Guo Y, Liu R, Yu Q, Gong L, Liu Z, Xie W, Wang C Biochem Pharmacol. 2020 Oct 14:114284. doi: 10.1016/j.bcp.2020.114284. PMID:33068553[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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