Modularity of intrinsic disorder in the human proteome

Predicting regions of disorder has become of increasing interest when determining protein structure and function. With ∼33% of eukaryotic proteins having significant disordered regions, and an increasing occurrence of disorder in higher organisms, an analysis of the importance of disorder from an evolutionary perspective was clearly warranted. Focusing on the human proteome, we have studied how abundant disorder is and its relevance to protein function and structure. We have shown that disordered regions frequently appear to be independent functional units, and judged by complete association to certain protein domains, may be evolutionarily conserved. Our work also supports previous analyses on association between disorder and alternate splicing and provides support for the modularity of disorder by showing that with respect to splicing events, disordered regions frequently appear to be spliced as whole units. Proteins 2010. © 2009 Wiley‐Liss, Inc.

[1]  R. Reeves,et al.  Molecular biology of HMGA proteins: hubs of nuclear function. , 2001, Gene.

[2]  P. Romero,et al.  Conservation of intrinsic disorder in protein domains and families: I. A database of conserved predicted disordered regions. , 2006, Journal of Proteome Research.

[3]  P. Romero,et al.  Sequence complexity of disordered protein , 2001, Proteins.

[4]  Vladimir N Uversky,et al.  What does it mean to be natively unfolded? , 2002, European journal of biochemistry.

[5]  Christopher J. Oldfield,et al.  Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners , 2008, BMC Genomics.

[6]  Christine A. Orengo,et al.  Inferring Function Using Patterns of Native Disorder in Proteins , 2007, PLoS Comput. Biol..

[7]  V. Uversky.  Intrinsically Disordered Proteins , 2000 .

[8]  Debasis Dash,et al.  Role of intrinsic disorder in transient interactions of hub proteins , 2006, Proteins.

[9]  H. Dyson,et al.  Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. , 1999, Journal of molecular biology.

[10]  Christopher J. Oldfield,et al.  Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. , 2007, Journal of proteome research.

[11]  L. Iakoucheva,et al.  The importance of intrinsic disorder for protein phosphorylation. , 2004, Nucleic acids research.

[12]  Christopher J. Oldfield,et al.  Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling , 2005, Journal of molecular recognition : JMR.

[13]  Christopher J. Oldfield,et al.  Intrinsically disordered protein. , 2001, Journal of molecular graphics & modelling.

[14]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[15]  A Keith Dunker,et al.  Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions. , 2007, Journal of proteome research.

[16]  Christopher J. Oldfield,et al.  Intrinsic disorder in transcription factors. , 2006, Biochemistry.

[17]  Lilia M. Iakoucheva,et al.  Intrinsic Disorder Is a Common Feature of Hub Proteins from Four Eukaryotic Interactomes , 2006, PLoS Comput. Biol..

[18]  A Keith Dunker,et al.  Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[20]  J. S. Sodhi,et al.  Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. , 2004, Journal of molecular biology.

[21]  Zoran Obradovic,et al.  DisProt: the Database of Disordered Proteins , 2006, Nucleic Acids Res..

[22]  Sonia Longhi,et al.  Assessing protein disorder and induced folding , 2005, Proteins.

[23]  L. Iakoucheva,et al.  Intrinsic disorder in cell-signaling and cancer-associated proteins. , 2002, Journal of molecular biology.

[24]  Bernard F. Buxton,et al.  The DISOPRED server for the prediction of protein disorder , 2004, Bioinform..

[25]  P. Tompa.  Intrinsically unstructured proteins. , 2002, Trends in biochemical sciences.

[26]  Adam Godzik,et al.  Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences , 2006, Bioinform..

[27]  D. T. Jones,et al.  Sequence patterns associated with disordered regions in proteins , 2004, Proteins.

[28]  Christopher J. Oldfield,et al.  Intrinsic disorder and functional proteomics. , 2007, Biophysical journal.

[29]  A Keith Dunker,et al.  Intrinsic disorder and protein function. , 2002, Biochemistry.

[30]  A. Iglesias,et al.  Intrinsic disorder is a key characteristic in partners that bind 14‐3‐3 proteins , 2006, Proteins.

[31]  H. Dyson,et al.  Intrinsically unstructured proteins and their functions , 2005, Nature Reviews Molecular Cell Biology.

[32]  W R Taylor,et al.  A model recognition approach to the prediction of all-helical membrane protein structure and topology. , 1994, Biochemistry.

[33]  V. Uversky.  Natively unfolded proteins: A point where biology waits for physics , 2002, Protein science : a publication of the Protein Society.

[34]  D. Higgins,et al.  T-Coffee: A novel method for fast and accurate multiple sequence alignment. , 2000, Journal of molecular biology.

[35]  Zoran Obradovic,et al.  The protein trinity—linking function and disorder , 2001, Nature Biotechnology.

[36]  V. Uversky,et al.  Why are “natively unfolded” proteins unstructured under physiologic conditions? , 2000, Proteins.

[37]  Monika Fuxreiter,et al.  Close encounters of the third kind: disordered domains and the interactions of proteins , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[38]  Alexandra Poulovassilis,et al.  ISPIDER Central: an integrated database web-server for proteomics , 2008, Nucleic Acids Res..

[39]  Christopher J. Oldfield,et al.  Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. , 2007, Journal of proteome research.

[40]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[41]  David T. Jones,et al.  Improving the accuracy of transmembrane protein topology prediction using evolutionary information , 2007, Bioinform..

[42]  Z. Obradovic,et al.  Identification and functions of usefully disordered proteins. , 2002, Advances in protein chemistry.

[43]  R. Zimmer,et al.  Alternative splicing and protein structure evolution. , 2008, Nucleic acids research.