Abstract
The first crystal structure of mammalian monoamine oxidases (MAOs) was solved in 2002; almost 65 years after, these FAD-dependent enzymes were discovered and classified as responsible for the oxidation of aromatic neurotransmitters. Both MAO A and MAO B feature a two-domain topology characterized by the Rossmann fold, interacting with dinucleotide cofactors, which is intimately associated to a substrate-binding domain. This globular body is endowed with a C-terminal α-helix that anchors the protein to the outer mitochondrial phospholipid bilayer. As monotopic membrane proteins, the structural elucidation of MAOs was a challenging task that required the screening of different detergent conditions for their purification and crystallization. MAO A and MAO B structures differ both in their oligomerization architecture and in details of their active sites. Purified human MAO B and rat MAO A are dimeric, whereas human MAO A was found to be monomeric, which is believed to result from the detergent treatments used to extract the protein from the membrane. The active site of MAOs consists of a hydrophobic cavity located in front of the flavin cofactor and extending to the protein surface. Some structural features are highly conserved in the two isozymes, such as a Tyr–Tyr aromatic sandwich in front of the flavin ring and a Lys residue hydrogen-bonded to the cofactor N5 atom, whereas a pair of gating residues (Phe208/Ile335 in MAO A; Ile199/Tyr326 in MAO B) specifically determines the different substrate and inhibitor properties of the two enzymes.
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(source: Membrane Proteins of Known 3D Structures, http://blanco.biomol.uci.edu/mpstruc/) is depicted within its native membrane compartment, either in the prokaryotic (left) or in the eukaryotic (right) cell
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Abbreviations
- MAO:
-
Monoamine oxidase
- FAD:
-
Flavin adenine dinucleotide
- ROS:
-
Reactive oxygen species
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Acknowledgements
This work was supported by Fondazione Cariplo (Grant no. 2014 − 0672 to C.B.) and by the Italian Ministry of Education, University and Research (MIUR, “Dipartimenti di Eccellenza Program 2018–2022—Dept. of Biology and Biotechnology L. Spallanzani”, University of Pavia).
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Iacovino, L.G., Magnani, F. & Binda, C. The structure of monoamine oxidases: past, present, and future. J Neural Transm 125, 1567–1579 (2018). https://doi.org/10.1007/s00702-018-1915-z
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DOI: https://doi.org/10.1007/s00702-018-1915-z