Methionine-Rich Loop of Multicopper Oxidase McoA Follows Open-to-Close Transitions with
a Role in Enzyme Catalysis
Posted on 2020-06-17 - 17:43
Multicopper
oxidases oxidize a vast range of aromatic substrates
coupled to the reduction of molecular oxygen to water. A vast broad
spectrum of applications reflects their high biotechnological importance.
The crystal structure of McoA from the hyperthermophilic bacteria Aquifex aeolicus has the most tightly compact and
hydrophobic core among its prokaryotic counterparts. A 29-residue
long loop enriched in glycines and methionines (Met-loop) close to
the active T1 Cu center is not detected in the electron density maps.
Accurate prediction of loop structures remains challenging, especially
for long segments with sizable conformational space. Therefore, a
combination of Rosetta and molecular dynamics simulations with ensemble-based
small-angle X-ray scattering analysis was used to probe the conformational
landscape of the Met-loop. The results indicate a highly flexible
omega-loop, which is nevertheless not random but preferentially follows
open-to-close transitions, exposing or occluding the T1 Cu site. Loop-truncated
variants maintain wild-type stability and consistently lower and higher
catalytic efficiencies (kcat/Km) for organic and metal substrates, respectively. Our
results suggest that the loop transient dynamic equilibrium can exert
important switch-like regulatory function, defining a role for Met-rich
motifs as dynamic gate-gappers. This work provides insights into the
dynamics of Met-rich loops essential to understand the molecular determinants
of substrate promiscuity and catalytic rates within multicopper oxidases.
We anticipate that engineering the Met-loop structural dynamics will
unleash important changes in enzyme function and specificity with
impact on their applications.
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Borges, Patrícia
T.; Brissos, Vânia; Hernandez, Guillem; Masgrau, Laura; Lucas, Maria Fátima; Monza, Emanuele; et al. (2020). Methionine-Rich Loop of Multicopper Oxidase McoA Follows Open-to-Close Transitions with
a Role in Enzyme Catalysis. ACS Publications. Collection. https://doi.org/10.1021/acscatal.0c01623