Protein stability and dynamics modulation: the case of human frataxin

Mostrar todas las versiones(2)

Frataxin (FXN) is an α/β protein that plays an essential role in iron homeostasis. Apparently, the function of human FXN (hFXN) depends on the cooperative formation of crucial interactions between helix α1, helix α2, and the C-terminal region (CTR) of the protein. In this work we quantitatively expl...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Roman, Ernesto A., Faraj, Santiago E., Gallo, Mariana, Salvay, Andrés Gerardo, Ferreiro, Diego U., Santos, Javier
Formato: Articulo
Lenguaje:Inglés
Publicado: 2012
Materias:
Ciencias Exactas
Química
Física
Proteínas
Homeostasis
Hierro
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/29715
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045743
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-29715
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Exactas
Química
Física
Proteínas
Homeostasis
Hierro
spellingShingle Ciencias Exactas
Química
Física
Proteínas
Homeostasis
Hierro
Roman, Ernesto A.
Faraj, Santiago E.
Gallo, Mariana
Salvay, Andrés Gerardo
Ferreiro, Diego U.
Santos, Javier
Protein stability and dynamics modulation: the case of human frataxin
topic_facet Ciencias Exactas
Química
Física
Proteínas
Homeostasis
Hierro
description Frataxin (FXN) is an α/β protein that plays an essential role in iron homeostasis. Apparently, the function of human FXN (hFXN) depends on the cooperative formation of crucial interactions between helix α1, helix α2, and the C-terminal region (CTR) of the protein. In this work we quantitatively explore these relationships using a purified recombinant fragment hFXN90-195. This variant shows the hydrodynamic behavior expected for a monomeric globular domain. Circular dichroism, fluorescence, and NMR spectroscopies show that hFXN90-195 presents native-like secondary and tertiary structure. However, chemical and temperature induced denaturation show that CTR truncation significantly destabilizes the overall hFXN fold. Accordingly, limited proteolysis experiments suggest that the native-state dynamics of hFXN90-195 and hFXN90-210 are indeed different, being the former form much more sensitive to the protease at specific sites. The overall folding dynamics of hFXN fold was further explored with structure-based protein folding simulations. These suggest that the native ensemble of hFXN can be decomposed in at least two substates, one with consolidation of the CTR and the other without consolidation of the CTR. Explicit-solvent all atom simulations identify some of the proteolytic target sites as flexible regions of the protein. We propose that the local unfolding of CTR may be a critical step for the global unfolding of hFXN, and that modulation of the CTR interactions may strongly affect hFXN physiological function.
format Articulo
Articulo
author Roman, Ernesto A.
Faraj, Santiago E.
Gallo, Mariana
Salvay, Andrés Gerardo
Ferreiro, Diego U.
Santos, Javier
author_facet Roman, Ernesto A.
Faraj, Santiago E.
Gallo, Mariana
Salvay, Andrés Gerardo
Ferreiro, Diego U.
Santos, Javier
author_sort Roman, Ernesto A.
title Protein stability and dynamics modulation: the case of human frataxin
title_short Protein stability and dynamics modulation: the case of human frataxin
title_full Protein stability and dynamics modulation: the case of human frataxin
title_fullStr Protein stability and dynamics modulation: the case of human frataxin
title_full_unstemmed Protein stability and dynamics modulation: the case of human frataxin
title_sort protein stability and dynamics modulation: the case of human frataxin
publishDate 2012
url http://sedici.unlp.edu.ar/handle/10915/29715
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045743
work_keys_str_mv AT romanernestoa proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
AT farajsantiagoe proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
AT gallomariana proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
AT salvayandresgerardo proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
AT ferreirodiegou proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
AT santosjavier proteinstabilityanddynamicsmodulationthecaseofhumanfrataxin
bdutipo_str Repositorios
_version_ 1764820468158693376

Ejemplares similares