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The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.

Wang G, He Q, Feng C, Liu Y, Deng Z, Qi X, Wu W, Mei P, Chen Z
J Biol Chem 289 27924-36 (2014)
Related entries: 4qkb, 4qkd

Cited: 24 times
EuropePMC logo PMID: 25122757

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.

Articles - 4qkf mentioned but not cited (1)

  1. The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism. Wang G, He Q, Feng C, Liu Y, Deng Z, Qi X, Wu W, Mei P, Chen Z. J Biol Chem 289 27924-27936 (2014)


Reviews citing this publication (9)

  1. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond. Fedeles BI, Singh V, Delaney JC, Li D, Essigmann JM. J Biol Chem 290 20734-20742 (2015)
  2. RNA-modifying proteins as anticancer drug targets. Boriack-Sjodin PA, Ribich S, Copeland RA. Nat Rev Drug Discov 17 435-453 (2018)
  3. Non-homologous functions of the AlkB homologs. Ougland R, Rognes T, Klungland A, Larsen E. J Mol Cell Biol 7 494-504 (2015)
  4. Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family. Xu B, Liu D, Liu D, Wang Z, Tian R, Zuo Y. Cell Mol Life Sci 78 129-141 (2021)
  5. N(6)-Methyladenine in eukaryotes. Alderman MH, Xiao AZ. Cell Mol Life Sci 76 2957-2966 (2019)
  6. Structural Insights Into m6A-Erasers: A Step Toward Understanding Molecule Specificity and Potential Antiviral Targeting. Bayoumi M, Munir M, Munir M. Front Cell Dev Biol 8 587108 (2020)
  7. Exploring links between 2-oxoglutarate-dependent oxygenases and Alzheimer's disease. Liu H, Xie Y, Wang X, Abboud MI, Ma C, Ge W, Schofield CJ. Alzheimers Dement 18 2637-2668 (2022)
  8. Spectroscopic and in vitro Investigations of Fe2+ /α-Ketoglutarate-Dependent Enzymes Involved in Nucleic Acid Repair and Modification. Schmidl D, Lindlar Né Jonasson NSW, Menke A, Schneider S, Daumann LJ. Chembiochem 23 e202100605 (2022)
  9. The role of demethylase AlkB homologs in cancer. Li Q, Zhu Q. Front Oncol 13 1153463 (2023)

Articles citing this publication (14)

  1. NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. Haag S, Sloan KE, Ranjan N, Warda AS, Kretschmer J, Blessing C, Hübner B, Seikowski J, Dennerlein S, Rehling P, Rodnina MV, Höbartner C, Bohnsack MT, Bohnsack MT. EMBO J 35 2104-2119 (2016)
  2. Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA. Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, Xiao A, Li H. Cell Res 30 197-210 (2020)
  3. Adaptive Response Enzyme AlkB Preferentially Repairs 1-Methylguanine and 3-Methylthymine Adducts in Double-Stranded DNA. Chen F, Tang Q, Bian K, Humulock ZT, Yang X, Jost M, Drennan CL, Essigmann JM, Li D. Chem Res Toxicol 29 687-693 (2016)
  4. ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing. Zhang LS, Xiong QP, Peña Perez S, Liu C, Wei J, Le C, Zhang L, Harada BT, Dai Q, Feng X, Hao Z, Wang Y, Dong X, Hu L, Wang ED, Pan T, Klungland A, Liu RJ, He C. Nat Cell Biol 23 684-691 (2021)
  5. ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding. Walker AR, Silvestrov P, Müller TA, Podolsky RH, Dyson G, Hausinger RP, Cisneros GA. PLoS Comput Biol 13 e1005345 (2017)
  6. A Pan-Cancer Analysis Reveals the Prognostic and Immunotherapeutic Value of ALKBH7. Chen K, Shen D, Tan L, Lai D, Han Y, Gu Y, Lu C, Gu X. Front Genet 13 822261 (2022)
  7. ALKBH7 mediates necrosis via rewiring of glyoxal metabolism. Kulkarni CA, Nadtochiy SM, Kennedy L, Zhang J, Chhim S, Alwaseem H, Murphy E, Fu D, Brookes PS. Elife 9 e58573 (2020)
  8. The crystal structure of the thiocyanate-forming protein from Thlaspi arvense, a kelch protein involved in glucosinolate breakdown. Gumz F, Krausze J, Eisenschmidt D, Backenköhler A, Barleben L, Brandt W, Wittstock U. Plant Mol Biol 89 67-81 (2015)
  9. Prediction of the molecular boundary and functionality of novel viral AlkB domains using homology modelling and principal component analysis. Moore C, Meng B. J Gen Virol 100 691-703 (2019)
  10. The interactome and proteomic responses of ALKBH7 in cell lines by in-depth proteomics analysis. Meng S, Zhan S, Dou W, Ge W. Proteome Sci 17 8 (2019)
  11. Evolutionary History of RNA Modifications at N6-Adenosine Originating from the R-M System in Eukaryotes and Prokaryotes. Liu C, Cao J, Zhang H, Yin J. Biology (Basel) 11 214 (2022)
  12. 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 298 101671 (2022)
  13. Genetic alterations in juvenile cervical clear cell adenocarcinoma unrelated to human papillomavirus. Su Y, Zhang Y, Zhou M, Zhang R, Chen S, Zhang L, Wang H, Zhang D, Zhang T, Li X, Zhang C, Wang B, Yuan S, Zhang M, Zhou Y, Cao L, Zhang M, Luo J. Front Med (Lausanne) 10 1211888 (2023)
  14. NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression. Xie S, Yuan L, Sui Y, Feng S, Li H, Li X. EMBO Rep 25 378-403 (2024)


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