Intrinsically disordered proteins in human diseases: Introducing the D 2 concept

Vladimir N. Uversky, Christopher J. Oldfield, A. Dunker

Research output: Contribution to journalArticle

737 Citations (Scopus)

Abstract

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 normative folding. IDPs, such as α-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 D2 (disorder in disorders) concept.

Original languageEnglish
Pages (from-to)215-246
Number of pages32
JournalAnnual Review of Biophysics
Volume37
DOIs
StatePublished - 2008

Fingerprint

Intrinsically Disordered Proteins
Proteins
Synucleins
Neurodegenerative diseases
Cell signaling
tau Proteins
Sexual Partners
Alternative Splicing
Amyloidosis
Drug Discovery
Post Translational Protein Processing
Medical problems
Neurodegenerative Diseases
Cardiovascular Diseases

Keywords

  • Conformational disease
  • Intrinsic disorder
  • Protein misfolding

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Medicine(all)
  • Biochemistry

Cite this

Intrinsically disordered proteins in human diseases : Introducing the D 2 concept. / Uversky, Vladimir N.; Oldfield, Christopher J.; Dunker, A.

In: Annual Review of Biophysics, Vol. 37, 2008, p. 215-246.

Research output: Contribution to journalArticle

Uversky, Vladimir N. ; Oldfield, Christopher J. ; Dunker, A. / Intrinsically disordered proteins in human diseases : Introducing the D 2 concept. In: Annual Review of Biophysics. 2008 ; Vol. 37. pp. 215-246.
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