Publication: Glicoproteínas de la envoltura del HCV: implicación del péptido fusogénico de E1 y de los dominios transmembrana en las propiedades estructurales y funcionales del complejo E1-E2
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2016-04-01
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Universidad Complutense de Madrid
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Abstract
El virus de la hepatitis C es la principal causa de muerte debida a complicaciones hepáticas derivadas de su infección, con 350 000 personas fallecidas al año. Hasta el momento, la variedad genotípica y la dificultad para trabajar con el virus aislado o sus proteínas constituyentes ha hecho imposible el desarrollo de una vacuna eficaz contra el HCV. En los últimos años se han llevado a cabo grandes avances en el tratamiento de la enfermedad con el desarrollo de nuevos fármacos capaces de alcanzar un nivel de curación superior al 96% para pacientes infectados con el genotipo 1, quedando el resto excluidos de estas terapias. El HCV pertenece a la familia Flaviviridae, y como tal, las glicoproteínas de la envoltura, E1 y E2, son las principales responsables del reconocimiento de receptores y la entrada en las células diana. E2 parece ser la proteína principal, mientras que E1, la proteína acompañante, funcionaría como una chaperona para el correcto plegamiento de la primera. Ambas interaccionan para dar lugar a un heterodímero funcional esencial para el ciclo viral. Sin embargo, la implicación de E1 en el reconocimiento y la fusión del complejo E1-E2 aún no ha sido determinada. En este sentido, existe una controversia sobre cuál es el proteína fusogénica. Así, diversos péptidos fusogénicos han sido descritos para E2, pero también ha sido propuesta una región hidrofóbica en E1, comprendiendo los residuos 268-292, como un péptido fusogénico que podría contribuir a las primeras etapas del ciclo infectivo. Por otro lado, se ha descrito la necesidad de obtener un heterodímero estable entre E1 y E2 para producir partículas infecciosas capaces de entrar en las células diana. El mecanismo que permite la interacción entre ambas no ha sido establecido. Hasta el momento no se ha descrito la presencia de interacciones covalentes entre E1 y E2 pero se ha postulado la necesidad de residuos específicos en los dominios transmembrana (TMD) de ambas proteínas para formar heterodímeros funcionales. Aunque hasta la fecha no se ha llevado a cabo una caracterización exhaustiva de los TMD de E1 y E2, se ha descrito la implicación de diferentes residuos y motivos de secuencia en la interacción entre ambos TMD: 1) la Lys en posición 370 de E1 y el Asp en posición 728 de E2 podrían dar lugar a la formación de un puente salino entre ellos, 2) el motivo GXXXG entre los residuos 354 y 358 ha sido definido como un motivo de heterodimerización y 3) la Arg en posición 730 de E2 podría estar implicada en interacciones de tipo electrostático...
The Hepatitis C Virus is the main cause of death due to hepatic complications derived from the infection. The number of deceased people can reach 350 000 every year. Until now, the genotypic variety and the difficulty of working with the isolated virus or its constituent proteins, has made impossible to develop an effective vaccine against HCV. Advances in the treatment of the disease have been achieved in the last years through the advent of new drugs able to reach a degree of cure above 96% for patients infected with genotype 1, leaving the rest of genotypes excluded from these therapies. As a Flaviviridae virus, the envelope glycoproteins E1 and E2 are the main responsible for recognition of receptors and entry into target cells. E2 seems to be the leading protein and E1 the companion one, functioning as a chaperone for the correct folding of E2, acting both of them as a functional heterodimer essential for the virus cycle. However, the exact roles of E1 in the recognition and fusion processes of the E1- E2 complex remain to be determined. In this sense, there is a controversy about the assignment of the fusion protein. Regarding this point, several fusogenic peptides have been described for E2, but also one hydrophobic region of E1, between residues 268 and 292, has been proposed as a fusogenic peptide which could contribute to the first stages of the infective cycle. On the other hand, it is known the need to obtain a stable heterodimer between E1 and E2 to produce infective particles able to enter in target cells. Moreover, the mechanism leading the interactions between E1 and E2 has not yet been well defined. Until now, any covalent interaction between E1 and E2 glycoproteins has not been described, but it has been postulated the necessity of specific residues in the transmembrane domains (TMD) of both proteins to form functional heterodimers. Although to date an exhaustive characterization of the E1 and E2 TMD has not been performed, it has been described the implication of different residues and motifs in the interaction between both of them. These are 1) the Lys in position 370 of E1 and the Asp in position 728 of E2 that could lead to the formation of a salt bridge between them, 2) the presence of a GXXXG sequence between residues 354 and 358 of E1 that has been defined as a dimerization motif and 3) the Arg residue at position 730 of E2 which could be implicated in another electrostatic interaction...
The Hepatitis C Virus is the main cause of death due to hepatic complications derived from the infection. The number of deceased people can reach 350 000 every year. Until now, the genotypic variety and the difficulty of working with the isolated virus or its constituent proteins, has made impossible to develop an effective vaccine against HCV. Advances in the treatment of the disease have been achieved in the last years through the advent of new drugs able to reach a degree of cure above 96% for patients infected with genotype 1, leaving the rest of genotypes excluded from these therapies. As a Flaviviridae virus, the envelope glycoproteins E1 and E2 are the main responsible for recognition of receptors and entry into target cells. E2 seems to be the leading protein and E1 the companion one, functioning as a chaperone for the correct folding of E2, acting both of them as a functional heterodimer essential for the virus cycle. However, the exact roles of E1 in the recognition and fusion processes of the E1- E2 complex remain to be determined. In this sense, there is a controversy about the assignment of the fusion protein. Regarding this point, several fusogenic peptides have been described for E2, but also one hydrophobic region of E1, between residues 268 and 292, has been proposed as a fusogenic peptide which could contribute to the first stages of the infective cycle. On the other hand, it is known the need to obtain a stable heterodimer between E1 and E2 to produce infective particles able to enter in target cells. Moreover, the mechanism leading the interactions between E1 and E2 has not yet been well defined. Until now, any covalent interaction between E1 and E2 glycoproteins has not been described, but it has been postulated the necessity of specific residues in the transmembrane domains (TMD) of both proteins to form functional heterodimers. Although to date an exhaustive characterization of the E1 and E2 TMD has not been performed, it has been described the implication of different residues and motifs in the interaction between both of them. These are 1) the Lys in position 370 of E1 and the Asp in position 728 of E2 that could lead to the formation of a salt bridge between them, 2) the presence of a GXXXG sequence between residues 354 and 358 of E1 that has been defined as a dimerization motif and 3) the Arg residue at position 730 of E2 which could be implicated in another electrostatic interaction...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 02-10-2015