Abundance of intrinsic disorder in protein associated with cardiovascular disease

Yugong Cheng, Tanguy LeGall, Christopher J. Oldfield, A. Dunker, Vladimir N. Uversky

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Evidence that many protein regions and even entire proteins lacking stable tertiary and/or secondary structure in solution (i.e., intrinsically disordered proteins) might be involved in protein-protein interactions, regulation, recognition, and signal transduction is rapidly accumulating. These signaling proteins play a crucial role in the development of several pathological conditions, including cancer. To test a hypothesis that intrinsic disorder is also abundant in cardiovascular disease (CVD), a data set of 487 CVD-related proteins was extracted from SWISS-PROT. CVD-related proteins are depleted in major order-promoting residues (Trp, Phe, Tyr, Ile, and Val) and enriched in some disorder-promoting residues (Arg, Gln, Ser, Pro, and Glu). The application of a neural network predictor of natural disordered regions (PONDR VL-XT) together with cumulative distribution function (CDF) analysis, charge-hydropathy plot (CH plot) analysis, and α-helical molecular recognition feature (α-MoRF) indicator revealed that CVD-related proteins are enriched in intrinsic disorder. In fact, the percentage of proteins with 30 or more consecutive residues predicted by PONDR VL-XT to be disordered was 57 ± 4% for CVD-associated proteins. This value is close that described earlier for signaling proteins (66 ± 6%) and is significantly larger than the content of intrinsic disorder in eukaryotic proteins from SWISS-PROT (47 ± 4%) and in nonhomologous protein segments with a well-defined three-dimensional structure (13 ± 4%). Furthermore, CDF and CH-plot analyses revealed that 120 and 36 CVD-related proteins, respectively, are wholly disordered. This high level of intrinsic disorder could be important for the function of CVD-related proteins and for the control and regulation of processes associated with cardiovascular disease. In agreement with this hypothesis, 198 α-MoRFs were predicted in 101 proteins from the CVD data set. A comparison of disorder predictions with the experimental structural and functional data for a subset of the CVD-associated proteins indicated good agreement between predictions and observations. Thus, our data suggest that intrinsically disordered proteins might play key roles in cardiovascular disease.

Original languageEnglish
Pages (from-to)10448-10460
Number of pages13
JournalBiochemistry
Volume45
Issue number35
DOIs
StatePublished - Sep 5 2006

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Cardiovascular Diseases
Proteins
Intrinsically Disordered Proteins
Protein Databases
Distribution functions
Molecular recognition
Signal transduction
Signal Transduction

ASJC Scopus subject areas

  • Biochemistry

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Abundance of intrinsic disorder in protein associated with cardiovascular disease. / Cheng, Yugong; LeGall, Tanguy; Oldfield, Christopher J.; Dunker, A.; Uversky, Vladimir N.

In: Biochemistry, Vol. 45, No. 35, 05.09.2006, p. 10448-10460.

Research output: Contribution to journalArticle

Cheng, Y, LeGall, T, Oldfield, CJ, Dunker, A & Uversky, VN 2006, 'Abundance of intrinsic disorder in protein associated with cardiovascular disease', Biochemistry, vol. 45, no. 35, pp. 10448-10460. https://doi.org/10.1021/bi060981d
Cheng, Yugong ; LeGall, Tanguy ; Oldfield, Christopher J. ; Dunker, A. ; Uversky, Vladimir N. / Abundance of intrinsic disorder in protein associated with cardiovascular disease. In: Biochemistry. 2006 ; Vol. 45, No. 35. pp. 10448-10460.
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abstract = "Evidence that many protein regions and even entire proteins lacking stable tertiary and/or secondary structure in solution (i.e., intrinsically disordered proteins) might be involved in protein-protein interactions, regulation, recognition, and signal transduction is rapidly accumulating. These signaling proteins play a crucial role in the development of several pathological conditions, including cancer. To test a hypothesis that intrinsic disorder is also abundant in cardiovascular disease (CVD), a data set of 487 CVD-related proteins was extracted from SWISS-PROT. CVD-related proteins are depleted in major order-promoting residues (Trp, Phe, Tyr, Ile, and Val) and enriched in some disorder-promoting residues (Arg, Gln, Ser, Pro, and Glu). The application of a neural network predictor of natural disordered regions (PONDR VL-XT) together with cumulative distribution function (CDF) analysis, charge-hydropathy plot (CH plot) analysis, and α-helical molecular recognition feature (α-MoRF) indicator revealed that CVD-related proteins are enriched in intrinsic disorder. In fact, the percentage of proteins with 30 or more consecutive residues predicted by PONDR VL-XT to be disordered was 57 ± 4{\%} for CVD-associated proteins. This value is close that described earlier for signaling proteins (66 ± 6{\%}) and is significantly larger than the content of intrinsic disorder in eukaryotic proteins from SWISS-PROT (47 ± 4{\%}) and in nonhomologous protein segments with a well-defined three-dimensional structure (13 ± 4{\%}). Furthermore, CDF and CH-plot analyses revealed that 120 and 36 CVD-related proteins, respectively, are wholly disordered. This high level of intrinsic disorder could be important for the function of CVD-related proteins and for the control and regulation of processes associated with cardiovascular disease. In agreement with this hypothesis, 198 α-MoRFs were predicted in 101 proteins from the CVD data set. A comparison of disorder predictions with the experimental structural and functional data for a subset of the CVD-associated proteins indicated good agreement between predictions and observations. Thus, our data suggest that intrinsically disordered proteins might play key roles in cardiovascular disease.",
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