Abstract
In the present work, we have used the papillomavirus E7 oncoprotein to pursue structure-function and evolutionary studies that take into account intrinsic disorder and the conformational diversity of globular domains. The intrinsically disordered (E7N) and globular (E7C) domains of E7 show similar degrees of conservation and co-evolution. We found that E7N can be described in terms of conserved and coevolving linear motifs separated by variable linkers, while sequence evolution of E7C is compatible with the known homodimeric structure yet suggests other activities for the domain. Within E7N, inter-residue relationships such as residue co-evolution and restricted intermotif distances map functional coupling and co-occurrence of linear motifs that evolve in a coordinate manner. Within E7C, additional cysteine residues proximal to the zinc-binding site may allow redox regulation of E7 function. Moreover, we describe a conserved binding site for disordered domains on the surface of E7C and suggest a putative target linear motif. Both homodimerization and peptide binding activities of E7C are also present in the distantly related host PHD domains, showing that these two proteins share not only structural homology but also functional similarities, and strengthening the view that they evolved from a common ancestor. Finally, we integrate the multiple activities and conformations of E7 into a hierarchy of structure-function relationships.
Highlights
Many traditional concepts of protein science were originally developed for globular domains and are challenged by intrinsically disordered domains [1]
These results indicated that a lack of globular structure did not necessarily lead to a lower degree of sequence conservation and co-evolution in the E7 protein
Our representation of the intrinsically disordered E7 contains a disordered N-terminal domain (E7N) domain (Figure 2) consists of a one-dimensional array of several short sequence alignments separated by unaligned linkers of varying lengths, reminiscent of the description of promoters as linear maps of transcription factor binding sites [52] and to the recently proposed concepts of ‘‘constrained disorder’’ and ‘‘flexible disorder’’ [53]
Summary
Many traditional concepts of protein science were originally developed for globular domains and are challenged by intrinsically disordered domains [1]. As opposed to globular domains, there is no general consensus for the representation of structure- function relationships in disordered domains. Evolutionary structural biology commonly describes globular domains in terms of a continuous sequence alignment with a low percentage of gaps [3]. The relationship between conservation, co-evolution and function in disordered domains, called ‘‘evolutionary unstructural biology’’ [5], is still unclear. Disordered domains are considered to present a lower degree of sequence conservation and co-evolution than globular domains [7,8,9] and have different amino acid substitution patterns [10,11,12]. The well-known dynamic nature of proteins should be considered for evolutionary models of globular domains containing linear motifs
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