TY - JOUR
T1 - The atomic resolution structure of human alkb homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism
AU - Wang, Guoqiang
AU - He, Qingzhong
AU - Feng, Chong
AU - Liu, Yang
AU - Deng, Zengqin
AU - Qi, Xiaoxuan
AU - Wu, Wei
AU - Mei, Pinchao
AU - Chen, Zhongzhou
N1 - Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology Inc.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2014/10/3
Y1 - 2014/10/3
N2 - 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 A or N-oxalylglycine at 2.0 A resolution. ALKBH7 possesses the conserved double-stranded ß-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 ß-strands ß6 and ß7 and between ß9 and ß10 create a special outer wall of the minor ß-sheet of the double-stranded ß-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.
AB - 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 A or N-oxalylglycine at 2.0 A resolution. ALKBH7 possesses the conserved double-stranded ß-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 ß-strands ß6 and ß7 and between ß9 and ß10 create a special outer wall of the minor ß-sheet of the double-stranded ß-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.
UR - http://www.scopus.com/inward/record.url?scp=84907482246&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.590505
DO - 10.1074/jbc.M114.590505
M3 - Article
C2 - 25122757
AN - SCOPUS:84907482246
VL - 289
SP - 27924
EP - 27936
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 40
ER -