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Mapping Dysfunctional Protein-Protein Interactions in Disease
Published on: October 24, 2025
Intrinsically disordered proteins in human diseases: introducing the D2 concept
Vladimir N Uversky1, Christopher J Oldfield, A Keith Dunker
1Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. vuversky@iupui.edu
Annual Review of Biophysics
|June 25, 2008
Summary
Intrinsically disordered proteins (IDPs) are crucial for cell regulation and signaling. Their unique structure is linked to various diseases, offering new therapeutic targets for drug discovery.
Area of Science:
- Biochemistry and Molecular Biology
- Structural Biology
- Genetics
Background:
- Intrinsically disordered proteins (IDPs) lack stable structures, unlike conventional proteins.
- IDPs are abundant and play vital roles in cellular regulation, signaling, and control.
- Their functions are modulated by alternative splicing and posttranslational modifications.
Purpose of the Study:
- To explore the multifaceted roles of IDPs in biological systems.
- To highlight the connection between intrinsic disorder and human diseases.
- To introduce the D2 (disorder in disorders) concept for novel drug discovery strategies.
Main Methods:
- Literature review and synthesis of existing research on IDPs.
- Analysis of IDP involvement in signaling pathways and disease mechanisms.
- Case studies of specific IDPs like alpha-synuclein, tau, p53, and BRCA1.
Main Results:
- IDPs facilitate complex signaling through multi-partner binding and adaptable interactions.
- Dysregulation of IDPs is implicated in major human diseases, including cancer and neurodegeneration.
- IDPs represent promising targets for developing drugs that modulate protein-protein interactions.
Conclusions:
- Intrinsic disorder is a key feature enabling diverse protein functions and cellular processes.
- Protein conformational diseases can arise from issues beyond misfolding, including misidentification and missignaling.
- The D2 concept offers a framework for understanding and targeting IDPs in disease contexts.
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