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      Disease mutations in disordered regions--exception to the rule?

      Molecular Biosystems
      Animals, Databases, Protein, Disease, genetics, Humans, Mutation, Protein Conformation, Protein Folding, Proteins, chemistry, metabolism

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          Abstract

          Intrinsically disordered proteins (IDPs) have been implicated in a number of human diseases, including cancer, diabetes, neurodegenerative and cardiovascular disorders. Although for some of these conditions molecular mechanisms are now better understood, the big picture connecting distinct structural properties and functional repertoire of IDPs to pathogenesis and disease progression is still incomplete. Recent studies suggest that signaling and regulatory roles carried out by IDPs require them to be tightly regulated, and that altered IDP abundance may lead to disease. Here, we propose another link between IDPs and disease that takes into account disease-associated missense mutations located in the intrinsically disordered regions. We argue that such mutations are more prevalent and have larger functional impact than previously thought. In addition, we demonstrate that deleterious amino acid substitutions that cause disorder-to-order transitions are particularly enriched among disease mutations compared to neutral polymorphisms. Finally, we discuss potential differences in functional outcomes between disease mutations in ordered and disordered regions, and challenge the conventional structure-centric view of missense mutations.

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          Author and article information

          Journal
          22080206
          3307532
          10.1039/c1mb05251a

          Chemistry
          Animals,Databases, Protein,Disease,genetics,Humans,Mutation,Protein Conformation,Protein Folding,Proteins,chemistry,metabolism

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