Hidden Structural Codes in Protein Intrinsic Disorder

BORKOSKY, SILVIA S.; CAMPOREALE, GABRIELA; CHEMES, LUCÍA B.; RISSO, MARIKENA; NOVAL, MARÍA GABRIELA; SÁNCHEZ, IGNACIO E.; ALONSO, LEONARDO G.; DE PRAT GAY, GONZALO

BIOCHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2017

0006-2960

Intrinsic disorder is a major structural category in biology, accounting formore than 30% of coding regions across the domains of life, yet consists ofconformational ensembles in equilibrium, a major challenge in protein chemistry.Anciently evolved papillomavirus genomes constitute an unparalleled case for sequenceto structure−function correlation in cases in which there are no folded structures. E7, themajor transforming oncoprotein of human papillomaviruses, is a paradigmatic exampleamong the intrinsically disordered proteins. Analysis of a large number of sequences ofthe same viral protein allowed for the identification of a handful of residues with absoluteconservation, scattered along the sequence of its N-terminal intrinsically disordereddomain, which intriguingly are mostly leucine residues. Mutation of these led to apronounced increase in both α-helix and β-sheet structural content, reflected by drasticeffects on equilibrium propensities and oligomerization kinetics, and uncovers theexistence of local structural elements that oppose canonical folding. These folding relays suggest the existence of yet undefinedhidden structural codes behind intrinsic disorder in this model protein. Thus, evolution pinpoints conformational hot spots thatcould have not been identified by direct experimental methods for analyzing or perturbing the equilibrium of an intrinsicallydisordered protein ensemble.