Hidden Structural Codes in Protein Intrinsic Disorder

Abstract

Protein intrinsic disorder is a major structural category in biology yet its definition is often limited to the absence of folding. The explosion of information in the genomic era showed that it may account for over 30% of coding regions across life domains, and it is particularly overrepresented in viruses. Papillomaviruses are an unparalleled case for sequence to structure correlation analysis because of the existence of hundreds of anciently evolved and stable virus types which are divergent enough in sequence, but conserving the function of each protein. E7, the main transforming oncoprotein from human papillomaviruses, is a paradigmatic example of an intrinsically disordered protein with pathological moonlighting 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 marked increase in both α-helix and ß-sheet structural content, reflected by drastic effects on equilibrium propensities and oligomerization kinetics. These results strongly suggest the existence of local nuclei, yet to be defined in structural terms, that oppose to canonical folding as expected for globular proteins. Moreover, direct coupling analysis pinpoint interactions surprisingly coincident with the proposed nuclei. In addition, these match with regions of helix propensities found in TFE/NMR experiments.