Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D²concept

Abstract

Many biologically active proteins, which are usually called intrinsically disordered or natively unfolded proteins, lack stable tertiary and/or secondary structure under physiological conditions in vitro. Their functions complement the functional repertoire of ordered proteins, with intrinsically disordered proteins (IDPs) often being involved in regulation, signaling and control. Their amino acid sequences and compositions are very different from those of ordered proteins, making reliable identification of IDPs possible at the proteome level. IDPs are highly abundant in various human diseases, including neurodegeneration and other protein dysfunction maladies and, therefore, represent attractive novel drug targets. Some of the aspects of IDPs, as well as their roles in neurodegeneration and protein dysfunction diseases, are discussed in this article, together with the peculiarities of IDPs as potential drug targets. Keywordsdisorder-based drug discovery; disorder prediction; intrinsically disordered protein; molten globule; premolten globule; random coil Intrinsically disordered proteinsProteins play a number of crucial roles in the maintenance of life, and protein dysfunctions may cause the development of various pathological conditions. For a very long time it has been believed that the specific functionality of a given protein is predetermined by its unique 3D structure [1,2]. However, Figure 1 shows that, although many proteins are indeed predisposed to fold into unique structures, which evolved to possess unique biological functions, some proteins can misfold either spontaneously or owing to a number of factors, such as mutations and other genetic alterations, problematic processing or post-translational modifications, or exposure to harmful environmental conditions. Such misfolding is now Tel.: +1 317 278, 6448 Fax: +1 317 278 9217, vuversky@iupui.edu. Financial & competing interests disclosure This work was supported in part by the Program of the Russian Academy of Sciences for the 'Molecular and cellular biology', by grants R01 LM007688-01A1 and GM071714-01A2 from the National Institutes of Health, and by the grant EF 0849803 from the National Science Foundation. I gratefully acknowledge the support of the IUPUI Signature Centers Initiative. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access Author ManuscriptExpert Rev Proteomics. Author manuscript; available in PMC 2012 June 9. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript considered a crucial early step in the development of various protein conformation diseases [3]. Finally, many proteins (now widely known as intrinsically disordered proteins [IDPs]) possess no definite ordered 3D structure, but still play important biological roles...

Staphylococcus epidermidis small basic protein (Sbp) forms amyloid fibrils, consistent with its function as a scaffolding protein in biofilms

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“…We suggest that the unusual rod-like shape of the tetrameric protein in conjunction with the intrinsic disorder of the N terminus of each monomer contributes to its large apparent molecular mass upon gel filtration. Gel filtration data consistent with apparent mass greater than actual mass are expected for intrinsically disordered proteins because of increased hydrodynamic volume relative to that of ordered proteins of the same mass (51). However, the molecular mass of purified vaccinia-expressed H5 appears to be more complex with a heterogenous mix of protein structures ranging from tetramers to octamers and even higher order structures.…”