Intrinsic Disorder in the Human Papillomavirus E7 Protein

Chemes, Lucía B.; Sánchez, Ignacio E.; Alonso, Leonardo G.; Prat‐Gay, Gonzalo de

doi:10.1002/9781118135570.ch12

Cited by 7 publications

(9 citation statements)

References 135 publications

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“…1a) that can adopt a compact conformation in low concentrations of GdmCl 33 and can undergo structural transitions upon mild changes in the chemical environment. 31,33 Intrinsic disorder and conformational plasticity within E7 are thought to expand its interaction repertoire 31,33,43,44 and may allow for flexibility and speed 45 in accommodating the several interaction surfaces that participate in binding to Rb, but the influence of multiple binding sites and structural flexibility on the mechanism of interaction with Rb has not been explored to date. Other LxCxE-containing Rb partners also present multiple interaction sites, including viral proteins AdE1A and SV40-LT and cellular targets HDAC, EID-1 and CtIP, 11,[46][47][48][49][50][51] stressing the need for understanding their role on the interaction mechanism.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Recognition of the Retinoblastoma Tumor Suppressor by a Specific Protein Target

Chemes

Sánchez

Prat‐Gay

2011

Journal of Molecular Biology

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Section: Introductionmentioning

confidence: 99%

Kinetic Recognition of the Retinoblastoma Tumor Suppressor by a Specific Protein Target

Chemes

Sánchez

Prat‐Gay

2011

Journal of Molecular Biology

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“…We have been investigating its biochemical properties (structure-function) in connection with its biological role. The protein binds to a large number of cellular targets, and this property lies largely on its structural plasticity arising from the intrinsically disordered nature of its N-terminal domain, and in fact, it turned out to be an excellent model for IDPs [17] , [18] , [19] , [43] . A salient feature was its ability to self-assemble into spherical oligomers upon removal of a tetrahedrically coordinated zinc atom, and we showed that these structures are formed within cell lines and cancerous tissue [27] .…”

Section: Discussionmentioning

confidence: 99%

Ordered Self-Assembly Mechanism of a Spherical Oncoprotein Oligomer Triggered by Zinc Removal and Stabilized by an Intrinsically Disordered Domain

Smal

Alonso²,

Wetzler

et al. 2012

PLoS ONE

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BackgroundSelf-assembly is a common theme in proteins of unrelated sequences or functions. The human papillomavirus E7 oncoprotein is an extended dimer with an intrinsically disordered domain, that can form large spherical oligomers. These are the major species in the cytosol of HPV transformed and cancerous cells. E7 binds to a large number of targets, some of which lead to cell transformation. Thus, the assembly process not only is of biological relevance, but represents a model system to investigate a widely distributed mechanism.Methodology/Principal FindingsUsing various techniques, we monitored changes in secondary, tertiary and quaternary structure in a time course manner. By applying a robust kinetic model developed by Zlotnik, we determined the slow formation of a monomeric “Z-nucleus” after zinc removal, followed by an elongation phase consisting of sequential second-order events whereby one monomer is added at a time. This elongation process takes place at a strikingly slow overall average rate of one monomer added every 28 seconds at 20 µM protein concentration, strongly suggesting either a rearrangement of the growing complex after binding of each monomer or the existence of a “conformation editing” mechanism through which the monomer binds and releases until the appropriate conformation is adopted. The oligomerization determinant lies within its small 5 kDa C-terminal globular domain and, remarkably, the E7 N-terminal intrinsically disordered domain stabilizes the oligomer, preventing an insoluble amyloid route.ConclusionWe described a controlled ordered mechanism with features in common with soluble amyloid precursors, chaperones, and other spherical oligomers, thus sharing determining factors for symmetry, size and shape. In addition, such a controlled and discrete polymerization reaction provides a valuable tool for nanotechnological applications. Finally, its increased immunogenicity related to its supramolecular structure is the basis for the development of a promising therapeutic vaccine candidate for treating HPV cancerous lesions.

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“…Previous research has identified several such relationships for regulatory DNA sequence motifs in the viral genome. 10 Based on our previous studies, 11 we have identified the papillomavirus E7 protein as a useful model system to study the evolution of functional linear motifs for several reasons. First, E7 presents a disordered N-terminal domain (E7N) and a C-terminal domain with a globular homodimeric structure (E7C) [12][13][14][15] (Fig.…”

Section: Introductionmentioning

confidence: 99%