Disorder in a two-domain neuronal Ca 2+ -binding protein regulates domain stability and dynamics using ligand mimicry
Kemplen, Katherine R.
Heidarsson, Pétur O.
Cellular and Molecular Life Sciences
Springer International Publishing
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Staby, L., Kemplen, K. R., Stein, A., Ploug, M., Clarke, J., Skriver, K., Heidarsson, P. O., & et al. (2020). Disorder in a two-domain neuronal Ca 2+ -binding protein regulates domain stability and dynamics using ligand mimicry. Cellular and Molecular Life Sciences, 78 (5), 2263-2278. https://doi.org/10.1007/s00018-020-03639-z
Funder: Lundbeckfonden; doi: http://dx.doi.org/10.13039/501100003554
Funder: Villum Fonden (DK)
Abstract: Understanding the interplay between sequence, structure and function of proteins has been complicated in recent years by the discovery of intrinsically disordered proteins (IDPs), which perform biological functions in the absence of a well-defined three-dimensional fold. Disordered protein sequences account for roughly 30% of the human proteome and in many proteins, disordered and ordered domains coexist. However, few studies have assessed how either feature affects the properties of the other. In this study, we examine the role of a disordered tail in the overall properties of the two-domain, calcium-sensing protein neuronal calcium sensor 1 (NCS-1). We show that loss of just six of the 190 residues at the flexible C-terminus is sufficient to severely affect stability, dynamics, and folding behavior of both ordered domains. We identify specific hydrophobic contacts mediated by the disordered tail that may be responsible for stabilizing the distal N-terminal domain. Moreover, sequence analyses indicate the presence of an LSL-motif in the tail that acts as a mimic of native ligands critical to the observed order–disorder communication. Removing the disordered tail leads to a shorter life-time of the ligand-bound complex likely originating from the observed destabilization. This close relationship between order and disorder may have important implications for how investigations into mixed systems are designed and opens up a novel avenue of drug targeting exploiting this type of behavior.
Original Article, NCS-1, Frequenin, IDP, EF-hand, Protein folding, Order–disorder interplay
Novo Nordisk Fonden (NNF18OC0033926)
Statens Naturvidenskabelige Forskningsrad (4181-00344)
External DOI: https://doi.org/10.1007/s00018-020-03639-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/328127