Abstract
All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short α-helical molecular recognition element can be considered to behave as a ‘bead on a string’. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.
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Abbreviations
- BH:
-
Bcl-2 homology
- CDF:
-
cumulative distribution frequency
- IUP:
-
intrinsically unstructured protein
- TM:
-
transmembrane
- HSQC:
-
heteronuclear single quantum coherence
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Acknowledgements
We thank Bronwyn Carlisle for help with preparing the figures. Our research is supported by the Marsden Fund (NZ), Leukemia and Lymphoma Society (Specialized Centre for Research 7015-02), Australian NH&MRC (Program Grant 257502) and fellowship (DCSH) and US NCI (CA 80188).
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Hinds, M., Smits, C., Fredericks-Short, R. et al. Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 14, 128–136 (2007). https://doi.org/10.1038/sj.cdd.4401934
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DOI: https://doi.org/10.1038/sj.cdd.4401934
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