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
ISSN: 03014622





BIOPHYSICAL CHEMISTRY
Editorial
ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS, Países Bajos
Tipo de documento: Article
Volumen: 296 Número:
Páginas:
WOS Id: 000962213900001
ID de PubMed: 36905841

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