title: The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.
abstract: ALKBH7 is the mitochondrial AlkB family member that is required for alkylation- and oxidation-induced programmed necrosis. In contrast to the protective role of other AlkB family members after suffering alkylation-induced DNA damage, ALKBH7 triggers the collapse of mitochondrial membrane potential and promotes cell death. Moreover, genetic ablation of mouse Alkbh7 dramatically increases body weight and fat mass. Here, we present crystal structures of human ALKBH7 in complex with Mn(II) and α-ketoglutarate at 1.35 Å or N-oxalylglycine at 2.0 Å resolution. ALKBH7 possesses the conserved double-stranded β-helix fold that coordinates a catalytically active iron by a conserved HX(D/E) … Xn … H motif. Self-hydroxylation of Leu-110 was observed, indicating that ALKBH7 has the potential to catalyze hydroxylation of its substrate. Unlike other AlkB family members whose substrates are DNA or RNA, ALKBH7 is devoid of the "nucleotide recognition lid" which is essential for binding nucleobases, and thus exhibits a solvent-exposed active site; two loops between β-strands β6 and β7 and between β9 and β10 create a special outer wall of the minor β-sheet of the double-stranded β-helix and form a negatively charged groove. These distinct features suggest that ALKBH7 may act on protein substrate rather than nucleic acids. Taken together, our findings provide a structural basis for understanding the distinct function of ALKBH7 in the AlkB family and offer a foundation for drug design in treating cell death-related diseases and metabolic diseases.
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.affiliation: the Department of Biochemistry and Molecular Biology, National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: He
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Chong
authors.initials: C
authors.lastname: Feng
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Zengqin
authors.initials: Z
authors.lastname: Deng
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Qi
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: the Department of Biochemistry and Molecular Biology, National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
authors.forename: Pinchao
authors.initials: P
authors.lastname: Mei
authors.affiliation: From the State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193 and chenzhongzhou@cau.edu.cn.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000071496:AlkB Enzymes; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005223:Fats / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids; D008345:Manganese / Q000737:chemistry / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009336:Necrosis; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D014961:X-Ray Diffraction
chemical_list: D005223:Fats; D007656:Ketoglutaric Acids; D024101:Mitochondrial Proteins; D008345:Manganese; C582297:ALKBH7 protein, human; D000071496:AlkB Enzymes
keywords: ALKB; ALKBH7; Crystal Structure; Dioxygenase; Fatty Acid Metabolism; Necrosis (Necrotic Death); Obesity; Protein Hydroxylase; Self-Hydroxylation; X-ray Crystallography