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2014 ; 289
(40
): 27924-36
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The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein
for programmed necrosis and fat metabolism
#MMPMID25122757
Wang G
; He Q
; Feng C
; Liu Y
; Deng Z
; Qi X
; Wu W
; Mei P
; Chen Z
J Biol Chem
2014[Oct]; 289
(40
): 27924-36
PMID25122757
show ga
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 ?-ketoglutarate at 1.35 Å or N-oxalylglycine at 2.0 Å
resolution. ALKBH7 possesses the conserved double-stranded ?-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 ?-strands ?6 and ?7 and between ?9
and ?10 create a special outer wall of the minor ?-sheet of the double-stranded
?-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.