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Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family

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Abstract

AlkB homologs (ALKBH) are a family of specific demethylases that depend on Fe2+ and α-ketoglutarate to catalyze demethylation on different substrates, including ssDNA, dsDNA, mRNA, tRNA, and proteins. Previous studies have made great progress in determining the sequence, structure, and molecular mechanism of the ALKBH family. Here, we first review the multi-substrate selectivity of the ALKBH demethylase family from the perspective of sequence and structural evolution. The construction of the phylogenetic tree and the comparison of key loops and non-homologous domains indicate that the paralogs with close evolutionary relationship have similar domain compositions. The structures show that the lack and variations of four key loops change the shape of clefts to cause the differences in substrate affinity, and non-homologous domains may be related to the compatibility of multiple substrates. We anticipate that the new insights into selectivity determinants of the ALKBH family are useful for understanding the demethylation mechanisms.

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Acknowledgements

We are grateful to our laboratory colleagues for their assistance with the bioinformatics analysis; we would like to thank Kanglu Zhao for helping us to collect the protein datasets.

Funding

This work was supported by National Natural Science Foundation of China (No: 61702290, 61861036), Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NJYT-18-B01), and Fund for Excellent Young Scholars of Inner Mongolia (2017JQ04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Baofang Xu and Dongyang Liu have contributed equally to this study.

Authors and Affiliations

  1. The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot, 010070, China

    Baofang Xu, Dongyang Liu, Zerong Wang, Ruixia Tian & Yongchun Zuo

  2. Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing, 100093, China

    Dongyang Liu

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Dongyang Liu

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  1. Baofang Xu
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  2. Dongyang Liu
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  5. Yongchun Zuo
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Contributions

BX and DL completed the drawing and writing of the paper together, ZW and RT collected the existing data and literature, and YZ was responsible for the overall thinking of the paper.

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Correspondence to Yongchun Zuo.

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Xu, B., Liu, D., Wang, Z. et al. Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family. Cell. Mol. Life Sci. 78, 129–141 (2021). https://doi.org/10.1007/s00018-020-03594-9

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