Conformational stability of the deamidated and mutated human?B2-crystallin
Por:
Velasco-Bolom J.-L., Dominguez, Laura
Publicada:
1 may 2023
Ahead of Print:
1 mar 2023
Resumen:
Previous studies propose that genetic mutations and post-translational
modifications in protein crystallins pro-mote protein aggregation and
are considered significant risk factors for cataract formation. The beta
B2-crystallin (H beta B2C) forms a high proportion of proteins in the
human eye lens. Different congenital mutations and post-translational
deamidations in beta B2-crystallin have been reported and linked to
cataract formation. In this work, we employed extensive all-atom
molecular dynamics simulations to evaluate the conformational stability
of deamidated and mutated H beta B2C. Our results show critical changes
in the protein surface and its native contacts due to a modification in
the conformational equilibrium of these proteins. The double deamidated
(Q70E/Q162E) and single deamidated (Q70E) impact the well compact
conformation of the H beta B2C. These post-translational modifications
allow the exposure of the protein hydrophobic interface, which lead to
the exposure of electronegative residues. On the other hand, our
mutational studies showed that the S143F mutation modifies the
hydrogen-bond network of an antiparallel beta-sheet, unfolding the
C-terminal domain. Interestingly, the chain termination mutation (Q155X)
does not unfold the N-terminal domain. However, the resultant
conformation is more compact and avoids the exposure of the hydrophobic
interface. Our results provide valuable information about the first
steps of H beta B2C unfolding in the presence of deamidated amino acids
that have been reported to appear during aging. The findings reported in
this work are essential for the general knowledge of the initial steps
in the cataract formation mechanism, which may be helpful for the
further development of molecules with pharmacological potential against
cataract disease.
Filiaciones:
Velasco-Bolom J.-L.:
Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Dominguez, Laura:
Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
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