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Biochemistry. 2017 Oct 17;56(41):5560-5569. doi: 10.1021/acs.biochem.7b00721. Epub 2017 Oct 6.

Hidden Structural Codes in Protein Intrinsic Disorder.

Author information

1
Protein Structure-Function and Engineering Laboratory, Fundación Instituto Leloir and Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA) CONICET , Buenos Aires, Argentina.
2
Department of Microbiology, New York University , Alexandria Center for Life Sciences, New York, New York 10016, United States.
3
Protein Physiology Laboratory, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Universidad de Buenos Aires , Buenos Aires, Argentina.

Abstract

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

PMID:
28952717
DOI:
10.1021/acs.biochem.7b00721
[Indexed for MEDLINE]

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