(1) The lock-and-key model of protein interactions has dominated biology for more than a century, shaping how scientists study molecular communication and approach the development of novel therapeutics.
(2) However, over the last two decades, scientists have come to appreciate that protein structure is a spectrum.
(3) While some proteins exist in a structured or ordered state, others have ordered domains with disordered regions, and some are even fully disordered.1
(4) Unlike folded proteins, intrinsically disordered proteins lack a stable, three-dimensional structure. Instead, they exhibit conformational heterogeneity and interconvert between different states.
(5) Because of their shapeshifting capabilities, scientists struggled to capture intrinsically disordered proteins using conventional approaches for determining protein structure. Over the last two decades, nuclear magnetic resonance spectroscopy and new bioinformatics tools have allowed researchers to explore the conformational properties of intrinsically disordered proteins.1,2
(6) The field is now witnessing a paradigm shift in how scientists think about protein interactions whereby an intrinsically disordered protein has an ensemble of possible conformations that allows the protein to respond to the environment and drive different functions accordingly. By dissecting and decoding the biophysical principles that dictate the sequence-ensemble-function relationship, scientists hope to shed light on the role of intrinsically disordered proteins in human health and disease.
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- Oldfield CJ, Dunker AK. Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem. 2014;83:553-584.
- Holehouse AS, Kragelund BB. The molecular basis for cellular function of intrinsically disordered protein regions. Nat Rev Mol Cell Biol. 2024;25(3):187-211.
