Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2
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Issue Date
2022-11-12Author
Meier, Alex A.
Moon, Hee-Jung
Sabuncu, Sinan
Singh, Priya
Ronnebaum, Trey A.
Ou, Siyu
Douglas, Justin T.
Jackson, Timothy A.
Moënne-Loccoz, Pierre
Mure, Minae
Publisher
MDPI
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
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Lysyl oxidase-2 (LOXL2) is a Cu2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn2+-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu2+ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu2. We propose that LTQ resides within 2.9 Å of the active site of Cu2+ in the mature LOXL2, and both LTQ and Cu2+ are solvent-exposed.
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Citation
Meier, A.A.; Moon, H.-J.; Sabuncu, S.; Singh, P.; Ronnebaum, T.A.; Ou, S.; Douglas, J.T.; Jackson, T.A.; Moënne-Loccoz, P.; Mure, M. Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2. Int. J. Mol. Sci. 2022, 23, 13966. https://doi.org/10.3390/ijms232213966
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