Rethinking the capsid proteins of enveloped viruses : multifunctionality from genome packaging to genome transfection

© 2015 FEBSRegardless of the debate on whether there is a place for viruses in the tree of life, it is consensual that they co-evolve with their hosts under the pressure of genome minimization. The abundance of multifunctional viral structural proteins is a consequence of this pressure. The molecular key to multifunctionality is the existence of intrinsically disordered domains together with ordered domains in the same protein. Capsid proteins, the hallmark of viruses, are not exceptions because they have coexisting ordered and disordered domains that are crucial for multifunctionality. It is also frequent to find supercharged proteins (i.e. proteins for which the net charge per unit molecular mass is > +0.75/kDa) among viral capsid proteins. All flaviviruses having annotated proteins in the ExPASy Viralzone database have supercharged capsid proteins. Moreover, cell-penetrating sequences/domains are frequent in viral proteins, even when they are not supercharged. Altogether, the findings strongly suggest that the ability to translocate membranes was acquired, conserved and optimized throughout the evolution of some viral proteins as part of their multifunctionality. The fitness of capsid proteins to translocate membranes carrying genomes was experimentally demonstrated with dengue virus capsid protein. This protein is potentially able to help the fusion process and translocate the RNA genome across the hemifused membrane formed by the viral envelope and the endosomal membrane. In addition, one of the cell-penetrating domains of the capsid protein also has antibacterial activity. This may be reminiscent of parasitic bacteria–bacteria competition for the same host and shed light on the origins of enveloped viruses.The authors acknowledge funding from Fundação para a Ciência e Tecnologia (FCT, Portugal; project HIVER/0002/2013), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq, Brazil, Projects 471239/2012-7 and 306669/2013-7), Fundação Carlos Chagas Filho de Amparo -a Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil, Projects E-26/111.668/2013 and E-26/201.167/2014), and European Commission, Program H2020, Marie Skłodowska-Curie Actions (MSCA), RISE project grant 644167. M. Castanho acknowledges the support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil; Project PVE171/2012) and J. Freire acknowledges fellowship SFRH/BD/70423/2010 from FCT, Portugal. A. S. Veiga acknowledges FCT, Portugal, for funding within the FCT Investigator Programme (IF/00803/2012)