Hidden Structural Codes in Protein Intrinsic Disorder

DE PRAT GAY, GONZALO; SÁNCHEZ, IGNACIO E.; BORKOSKY, SILVIA S.; ALONSO, LEONARDO G.

Simposio; The 31st Annual Symposium of the Protein Society; 2017

Protein intrinsic disorder is a major structural category in biology yet its definition is often limited tothe absence of folding. The explosion of information in the genomic era showed that it may accountfor over 30% of coding regions across life domains, and it is particularly overrepresented in viruses.Papillomaviruses are are an unparalleled case for sequence to structure correlation analysis because ofthe existence of hundreds of anciently evolved and stable virus types which are divergent enough insequence, but conserving the function of each protein. E7, the main transforming oncoprotein fromhuman papillomaviruses, is a paradigmatic example of an intrinsically disordered protein with pathologicalmoonlighting activities evolved for hijacking cell cycle control. Despite of being intrinsically disordered,the N-terminal domain shows more conserved residues than the globular C-terminal domain.Mutation of five hyper conserved residues precisely distributed along the sequence lead to a markedincrease in both a-helix and ß-sheet structural content, reflected by drastic effects on equilibrium propensitiesand oligomerization kinetics. These results strongly suggest the existence of local nuclei, yetto be defined in structural terms, that oppose to canonical folding as expected for globular proteins.These anti-folding nuclei acting as folding relays represent a novel concept that must involve hiddenstructural codes for intrinsic disorder clearly distant from random coil ensembles.