Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu 2+ in the Active Site of Lysyl Oxidase-like 2.

Autor: Meier AA; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Moon HJ; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Sabuncu S; Department of Chemical Physiology and Biochemistry, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA., Singh P; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Ronnebaum TA; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Ou S; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Douglas JT; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Jackson TA; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA., Moënne-Loccoz P; Department of Chemical Physiology and Biochemistry, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA., Mure M; Department of Chemistry, The University of Kansas, Lawrence, KS 66045, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Nov 12; Vol. 23 (22). Date of Electronic Publication: 2022 Nov 12.
DOI: 10.3390/ijms232213966
Abstrakt: Lysyl oxidase-2 (LOXL2) is a Cu 2+ 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 Zn 2+ -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 Cu 2+ 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 Cu 2 . We propose that LTQ resides within 2.9 Å of the active site of Cu 2+ in the mature LOXL2, and both LTQ and Cu 2+ are solvent-exposed.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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