1. A Unique Carboxylic-Acid Hydrogen-Bond Network (CAHBN) Confers Glutaminyl Cyclase Activity on M28 Family Enzymes
- Author
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Tzu Ping Ko, Kai-Fa Huang, Jing-Siou Huang, Mao-Lun Wu, Hui-Ling Hsu, Kai-Cheng Hsu, Wan-Ling Hsieh, and Andrew H.-J. Wang
- Subjects
Archaeal Proteins ,Carboxylic acid ,Low-barrier hydrogen bond ,Carboxylic Acids ,Protein Data Bank (RCSB PDB) ,Sequence (biology) ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Animals ,Humans ,Databases, Protein ,Molecular Biology ,Phylogeny ,030304 developmental biology ,Ions ,Mammals ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,Hydrogen bond ,Hydrogen Bonding ,Exopeptidase ,Aminoacyltransferases ,Glutaminyl-Peptide Cyclotransferase ,Kinetics ,Enzyme ,Biochemistry ,Metals ,Multigene Family ,biology.protein ,030217 neurology & neurosurgery - Abstract
Proteins with sequence or structure similar to those of di-Zn exopeptidases are usually classified as the M28-family enzymes, including the mammalian-type glutaminyl cyclases (QCs). QC catalyzes protein N-terminal pyroglutamate formation, a posttranslational modification important under many physiological and pathological conditions, and is a drug target for treating neurodegenerative diseases, cancers and inflammatory disorders. Without functional characterization, mammalian QCs and their orthologs remain indistinguishable at the sequence and structure levels from other M28-family proteins, leading to few reported QCs. Here, we show that a low-barrier carboxylic-acid hydrogen-bond network (CAHBN) is required for QC activity and discriminates QCs from M28-family peptidases. We demonstrate that the CAHBN-containing M28 peptidases deposited in the PDB are indeed QCs. Our analyses identify several thousands of QCs from the three domains of life, and we enzymatically and structurally characterize several. For the first time, the interplay between a CAHBN and the binuclear metal-binding center of mammalian QCs is made clear. We found that the presence or absence of CAHBN is a key discriminator for the formation of either the mono-Zn QCs or the di-Zn exopeptidases. Our study helps explain the possible roles of QCs in life.
- Published
- 2021