Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation

Intrinsic disorder is abundant in viral genomes and provides conformational plasticity to its protein products. In order to gain insight into its structure-function relationships, we carried out a comprehensive analysis of structural propensities within the intrinsically disordered N-terminal domain...

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Autores principales: Noval, María G., Gallo, Mariana, Perrone, Sebastián, Salvay, Andrés Gerardo, Chemes, Lucía B., Prat-Gay, Gonzalo de
Formato: Articulo
Lenguaje:Inglés
Publicado: 2013
Materias:
Biología
Ciencias Naturales
Human papillomavirus type
Cellular transformation
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/85517
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-85517
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Ciencias Naturales
Human papillomavirus type
Cellular transformation
spellingShingle Biología
Ciencias Naturales
Human papillomavirus type
Cellular transformation
Noval, María G.
Gallo, Mariana
Perrone, Sebastián
Salvay, Andrés Gerardo
Chemes, Lucía B.
Prat-Gay, Gonzalo de
Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
topic_facet Biología
Ciencias Naturales
Human papillomavirus type
Cellular transformation
description Intrinsic disorder is abundant in viral genomes and provides conformational plasticity to its protein products. In order to gain insight into its structure-function relationships, we carried out a comprehensive analysis of structural propensities within the intrinsically disordered N-terminal domain from the human papillomavirus type-16 E7 oncoprotein (E7N). Two E7N segments located within the conserved CR1 and CR2 regions present transient α-helix structure. The helix in the CR1 region spans residues L8 to L13 and overlaps with the E2F mimic linear motif. The second helix, located within the highly acidic CR2 region, presents a pH-dependent structural transition. At neutral pH the helix spans residues P17 to N29, which include the retinoblastoma tumor suppressor LxCxE binding motif (residues 21-29), while the acidic CKII-PEST region spanning residues E33 to I38 populates polyproline type II (PII) structure. At pH 5.0, the CR2 helix propagates up to residue I38 at the expense of loss of PII due to charge neutralization of acidic residues. Using truncated forms of HPV-16 E7, we confirmed that pH-induced changes in α-helix content are governed by the intrinsically disordered E7N domain. Interestingly, while at both pH the region encompassing the LxCxE motif adopts α-helical structure, the isolated 21-29 fragment including this stretch is unable to populate an α-helix even at high TFE concentrations. Thus, the E7N domain can populate dynamic but discrete structural ensembles by sampling α-helix-coil-PII-ß-sheet structures. This high plasticity may modulate the exposure of linear binding motifs responsible for its multi-target binding properties, leading to interference with key cell signaling pathways and eventually to cellular transformation by the virus.
format Articulo
Articulo
author Noval, María G.
Gallo, Mariana
Perrone, Sebastián
Salvay, Andrés Gerardo
Chemes, Lucía B.
Prat-Gay, Gonzalo de
author_facet Noval, María G.
Gallo, Mariana
Perrone, Sebastián
Salvay, Andrés Gerardo
Chemes, Lucía B.
Prat-Gay, Gonzalo de
author_sort Noval, María G.
title Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
title_short Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
title_full Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
title_fullStr Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
title_full_unstemmed Conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
title_sort conformational dissection of a viral intrinsically disordered domain involved in cellular transformation
publishDate 2013
url http://sedici.unlp.edu.ar/handle/10915/85517
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