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MODELLING OF 3D-STRUCTURES OF THE RARE MELANOCORTIN-1-RECEPTOR MUTATIONS ASSOCIATED TO MELANISM IN THE BANANAQUIT
MODELADO DE ESTRUCTURAS-3D DE MUTACIONES RARAS DEL RECEPTOR-1-MELANOCORTINA ASOCIADAS AL MELANISMO EN EL MIELERO
MODELAGEM DE ESTRUTURAS-3D DE MUTAÇÕES RARAS DO RECEPTOR-1-MELANOCORTINA ASSOCIADAS AO MELANISMO NO MIELERO
DOI:
https://doi.org/10.15446/abc.v26n1.81432Palabras clave:
Birds, Eumelanin, E92K, Protein Evolution, 3D-folding (en)Aves, Eumelanina, Evolución de Proteínas, E92K, Torción-3D (es)
Pássaros, Eumelanina, Evolução de Proteínas, E92K, Torción-3D (pt)
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Melanism in plumage color is often associated to the single nucleotide polymorphism of the melanocortin-1-receptor (MC1R). Despite the striking association between the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R protein and a completely black plumage, an in-depth understanding of the effect of missense mutations on the conformational change and behavior of the MC1R in the lipid bilayer caused by the absence of a crystal structure is lacking. We examine the structural basis for receptor activation using DNA sequences from the GenBank to perform in silicoprotein homology-based modeling. Our tridimensional model shows that the Alanine for a 179-Threoninesubstitution is a structural complement of the charge-reversing effect associated to the substitution of a Glutamic-acid by for a Lysine at position 92 on the MC1R. We proposed the possibility of gradual evolution in stability and electrostatic properties of the MC1R by the sequential accumulation of these two rare substitutions. These two rare substitutions further perturb physical-chemical properties that may be necessary folding requirements of the constitutively active MC1R forms without altering of ligand binding affinity. The computational coarse-grained molecular dynamics of the MC1R binding affinities to the melanocyte-stimulating hormone predicted the disparity in ligand binding amongalleles. We speculate that the disparity in structural constraints and ligand binding among the alleles within heterozygous individuals may contribute as a mechanism to the plumage color variation in the Coereba flaveola.
El melanismo en el color del plumaje se asocia frecuentemente al polimorfismo del receptor melanocortina-1(MC1R). La ausencia de una estructura cristalográfica de la asociación entre la sustitución del Glutamato por Lisina en la posición 92 de la proteína MC1R y el plumaje completamente negro, no ha permitido tener un mejor entendimiento del efecto de mutaciones no sinónimas en la conformación y en el comportamiento en la membrana del MC1R. Examinamos la estructura asociada a la activación del receptor usando secuencias de ADN obtenidas del GenBank, para un modelamiento in silicode formas homólogas de la proteína. El modelo tridimensional muestra que la sustitución de Alanina por la Treonina en la posición 179 es un complemento estructural al efecto de reversión de carga asociado a la sustitución del Glutamato por Lisina en la posición 92 del MC1R. Proponemos la posibilidad de evolución gradual de la estabilidad y de propiedades electrostáticas del MC1R por la acumulación de estas substituciones. Estas perturban las propiedades fisicoquímicas que podrían ser necesarias para el plegamiento de las formas constitutivamente activas del MC1R sin alterar la afinidad de empalme con el ligando. La modelación computacional de la dinámica molecular de la afinidad de empalme del MC1R a la hormona estimulante de meloncitos predice la disparidad de la unión con el ligando entre alelos. Consideramos que posiblemente la disparidad entre alelos en heterocigotos en cuanto a restricciones estructurales y la unión con el ligando podría contribuir a la variación en el color del plumaje en Coereba flaveola.
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