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Human AlkB homolog ALKBH6 in complex with alpha-katoglutarate and Mn
Structural highlights
FunctionALKB6_HUMAN Probable dioxygenase that requires molecular oxygen, alpha-ketoglutarate and iron. Publication Abstract from PubMedHuman AlkB homologue 6, ALKBH6, plays key roles in nucleic acid damage repair and tumor therapy. However, no precise structural and functional information are available for this protein. In this study, we determined atomic resolution crystal structures of human holo-ALKBH6 and its complex with ligands. AlkB members bind nucleic acids by NRLs (nucleotide recognition lids, also called Flips) which can recognize DNA/RNA and flip methylated lesions. We found that ALKBH6 has unusual Flip1 and Flip2 domains, distinct from other AlkB family members both in sequence and conformation. Moreover, we show that its unique Flip3 domain has multiple unreported functions, such as discriminating against double-stranded nucleic acids, blocking the active center, binding other proteins, and in suppressing tumor growth. Structure analyses and substrate screening reveal how ALKBH6 discriminates between different types of nucleic acids and may also function as a nucleic acid demethylase. Interestingly, structure-based interacting partner screening not only uncovered an unidentified interaction of transcription repressor ZMYND11 and ALKBH6 in tumor suppression, but also reveals crosstalk between histone modification and nucleic acid modification in epigenetic regulation. Taken together, these results shed light on the molecular mechanism underlying ALKBH6-associated nucleic acid damage repair and tumor therapy. Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6.,Ma L, Lu H, Tian Z, Yang M, Ma J, Shang G, Liu Y, Xie M, Wang G, Wu W, Zhang Z, Dai S, Chen Z J Biol Chem. 2022 Feb 1:101671. doi: 10.1016/j.jbc.2022.101671. PMID:35120926[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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