Frataxin (FXN) is a highly conserved protein found in prokaryotes and eukaryotes that is required for efficient regulation of cellular iron homeostasis. Experimental evidence associates amino acid substitutions of the FXN to Friedreich Ataxia, a neurodegenerative disorder. Recently, new thermodynamic experiments have been performed to study the impact of somatic variations identified in cancer tissues on protein stability. The Critical Assessment of Genome Interpretation (CAGI) data provider at the University of Rome measured the unfolding free energy of a set of variants (FXN challenge data set) with far-UV circular dichroism and intrinsic fluorescence spectra. These values have been used to calculate the change in unfolding free energy between the variant and wild-type proteins at zero concentration of denaturant formula presented . The FXN challenge data set, composed of eight amino acid substitutions, was used to evaluate the performance of the current computational methods for predicting the formula presented value associated with the variants and to classify them as destabilizing and not destabilizing. For the fifth edition of CAGI, six independent research groups from Asia, Australia, Europe, and North America submitted 12 sets of predictions from different approaches. In this paper, we report the results of our assessment and discuss the limitations of the tested algorithms.

Evaluating the predictions of the protein stability change upon single amino acid substitutions for the FXN CAGI5 challenge

Casadio, Rita;Fariselli, Piero;
2019-01-01

Abstract

Frataxin (FXN) is a highly conserved protein found in prokaryotes and eukaryotes that is required for efficient regulation of cellular iron homeostasis. Experimental evidence associates amino acid substitutions of the FXN to Friedreich Ataxia, a neurodegenerative disorder. Recently, new thermodynamic experiments have been performed to study the impact of somatic variations identified in cancer tissues on protein stability. The Critical Assessment of Genome Interpretation (CAGI) data provider at the University of Rome measured the unfolding free energy of a set of variants (FXN challenge data set) with far-UV circular dichroism and intrinsic fluorescence spectra. These values have been used to calculate the change in unfolding free energy between the variant and wild-type proteins at zero concentration of denaturant formula presented . The FXN challenge data set, composed of eight amino acid substitutions, was used to evaluate the performance of the current computational methods for predicting the formula presented value associated with the variants and to classify them as destabilizing and not destabilizing. For the fifth edition of CAGI, six independent research groups from Asia, Australia, Europe, and North America submitted 12 sets of predictions from different approaches. In this paper, we report the results of our assessment and discuss the limitations of the tested algorithms.
2019
40
9
1392
1399
free energy change; machine learning; protein folding; protein stability; single amino acid variant;
Savojardo, Castrense; Petrosino, Maria; Babbi, Giulia; Bovo, Samuele; Corbi‐Verge, Carles; Casadio, Rita; Fariselli, Piero; Folkman, Lukas; Garg, Aditi; Karimi, Mostafa; Katsonis, Panagiotis; Kim, Philip M.; Lichtarge, Olivier; Martelli, Pier Luigi; Pasquo, Alessandra; Pal, Debnath; Shen, Yang; Strokach, Alexey V.; Turina, Paola; Zhou, Yaoqi; Andreoletti, Gaia; Brenner, Steven; Chiaraluce, Roberta; Consalvi, Valerio; Capriotti, Emidio
File in questo prodotto:
File Dimensione Formato  
Savojardo_et_al-2019-Human_Mutation.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 627.55 kB
Formato Adobe PDF
627.55 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1706441
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 10
social impact