Journal
ANNUAL REVIEW OF BIOPHYSICS
Volume 37, Issue -, Pages 215-246Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev.biophys.37.032807.125924
Keywords
conformational disease; protein misfolding; intrinsic disorder
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Funding
- NIGMS NIH HHS [GM071714-01A2] Funding Source: Medline
- NLM NIH HHS [R01 LM007688-01A1] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM071714] Funding Source: NIH RePORTER
- NATIONAL LIBRARY OF MEDICINE [R01LM007688] Funding Source: NIH RePORTER
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Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their functional repertoire complements the functions of ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Functions of IDPs are tuned via alternative splicing and posttranslational modifications. Intrinsic disorder is a unique structural feature that enables IDPs to participate in both one-to-many and many-to-one signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conformational diseases may result not only from protein misfolding, but also from misidentification, missignaling, and unnatural or nonnative folding. IDPs, such as alpha-synuclein, tau protein, p53, and BRCA1, are attractive targets for drugs modulating protein-protein interactions. From these and other examples, novel strategies for drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D-2 (disorder in disorders) concept.
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