Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure

Craig Alan Gough, Keiichi Homma, Yumi Yamaguchi-Kabata, Makoto K. Shimada, Ranajit Chakraborty, Yasuyuki Fujii, Hisakazu Iwama, Shinsei Minoshima, Shigetaka Sakamoto, Yoshiharu Sato, Yoshiyuki Suzuki, Masahito Tada-Umezaki, Ken Nishikawa, Tadashi Imanishi, Takashi Gojobori

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequence polymorphisms which cause premature termination of a protein's sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set (n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of translation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of the locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual annotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the frameshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer which truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to diseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be useful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects.

Original languageEnglish
Article numbere50445
JournalPLoS One
Volume7
Issue number11
DOIs
Publication statusPublished - 26-11-2012

Fingerprint

protein structure
Polymorphism
genetic polymorphism
prediction
single nucleotide polymorphism
Proteins
proteins
Single Nucleotide Polymorphism
Nucleotides
amino acid substitution
Agglomeration
Genes
human diseases
transposons
Protein Databases
translation (genetics)
Sequence Deletion
Poisons
Amino Acid Substitution
amino acid sequences

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Gough, C. A., Homma, K., Yamaguchi-Kabata, Y., Shimada, M. K., Chakraborty, R., Fujii, Y., ... Gojobori, T. (2012). Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure. PLoS One, 7(11), [e50445]. https://doi.org/10.1371/journal.pone.0050445
Gough, Craig Alan ; Homma, Keiichi ; Yamaguchi-Kabata, Yumi ; Shimada, Makoto K. ; Chakraborty, Ranajit ; Fujii, Yasuyuki ; Iwama, Hisakazu ; Minoshima, Shinsei ; Sakamoto, Shigetaka ; Sato, Yoshiharu ; Suzuki, Yoshiyuki ; Tada-Umezaki, Masahito ; Nishikawa, Ken ; Imanishi, Tadashi ; Gojobori, Takashi. / Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure. In: PLoS One. 2012 ; Vol. 7, No. 11.
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Gough, CA, Homma, K, Yamaguchi-Kabata, Y, Shimada, MK, Chakraborty, R, Fujii, Y, Iwama, H, Minoshima, S, Sakamoto, S, Sato, Y, Suzuki, Y, Tada-Umezaki, M, Nishikawa, K, Imanishi, T & Gojobori, T 2012, 'Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure', PLoS One, vol. 7, no. 11, e50445. https://doi.org/10.1371/journal.pone.0050445

Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure. / Gough, Craig Alan; Homma, Keiichi; Yamaguchi-Kabata, Yumi; Shimada, Makoto K.; Chakraborty, Ranajit; Fujii, Yasuyuki; Iwama, Hisakazu; Minoshima, Shinsei; Sakamoto, Shigetaka; Sato, Yoshiharu; Suzuki, Yoshiyuki; Tada-Umezaki, Masahito; Nishikawa, Ken; Imanishi, Tadashi; Gojobori, Takashi.

In: PLoS One, Vol. 7, No. 11, e50445, 26.11.2012.

Research output: Contribution to journalArticle

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T1 - Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure

AU - Gough, Craig Alan

AU - Homma, Keiichi

AU - Yamaguchi-Kabata, Yumi

AU - Shimada, Makoto K.

AU - Chakraborty, Ranajit

AU - Fujii, Yasuyuki

AU - Iwama, Hisakazu

AU - Minoshima, Shinsei

AU - Sakamoto, Shigetaka

AU - Sato, Yoshiharu

AU - Suzuki, Yoshiyuki

AU - Tada-Umezaki, Masahito

AU - Nishikawa, Ken

AU - Imanishi, Tadashi

AU - Gojobori, Takashi

PY - 2012/11/26

Y1 - 2012/11/26

N2 - The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequence polymorphisms which cause premature termination of a protein's sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set (n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of translation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of the locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual annotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the frameshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer which truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to diseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be useful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects.

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