Using Protein Design Algorithms to Understand the Molecular Basis of Disease Caused by Protein-DNA Interactions: the Pax6 Example

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2010 Aug 6

PMID 20685816

Citations 36

Authors

Andreu Alibes

Alejandro D Nadra

Federico De Masi

Martha L Bulyk

Luis Serrano

Francois Stricher

Affiliations

Soon will be listed here.

Abstract

Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88% of the Pax6 mutations can be linked to changes in intrinsic stability (77%) and/or to its capabilities to bind DNA (30%). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.

Citing Articles

The Systemic Genotype-Phenotype Characterization of PAX6-Related Eye Disease in 164 Chinese Families.

Jiang Y, Yi Z, Zheng Y, Ouyang J, Guo D, Li S Invest Ophthalmol Vis Sci. 2024; 65(10):46.

PMID: 39212610 PMC: 11364179. DOI: 10.1167/iovs.65.10.46.

An Unusual Presentation of Novel Missense Variant in Gene: NM_000280.4:c.341A>G, p.(Asn114Ser).

Vasilyeva T, Sukhanova N, Khalanskaya O, Marakhonov A, Prokhorov N, Kadyshev V Curr Issues Mol Biol. 2024; 46(1):96-105.

PMID: 38248310 PMC: 10814852. DOI: 10.3390/cimb46010008.

Enhancing the thermostability of Streptomyces cyaneofuscatus strain Ms1 tyrosinase by multi-factors rational design and molecular dynamics simulations.

Li Z, Zhao C, Li D, Wang L PLoS One. 2023; 18(7):e0288929.

PMID: 37471348 PMC: 10358999. DOI: 10.1371/journal.pone.0288929.

ChromDL: A Next-Generation Regulatory DNA Classifier.

Hill C, Hudaiberdiev S, Ovcharenko I bioRxiv. 2023; .

PMID: 36789431 PMC: 9928050. DOI: 10.1101/2023.01.27.525971.

Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene.

Boehm B, Kratzer W, Bansal V Eur J Hum Genet. 2022; 31(1):89-96.

PMID: 36202929 PMC: 9823100. DOI: 10.1038/s41431-022-01182-y.

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