Disorder in a two-domain neuronal Ca 2+ -binding protein regulates domain stability and dynamics using ligand mimicry
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Disorder in a two‑domain neuronal Ca2+‑binding protein regulates domain stability and dynamics using ligand mimicry Lasse Staby1 · Katherine R. Kemplen1 · Amelie Stein1 · Michael Ploug2,3 · Jane Clarke4 · Karen Skriver1 · Pétur O. Heidarsson5 · Birthe B. Kragelund1 Received: 13 March 2020 / Revised: 8 August 2020 / Accepted: 3 September 2020 © The Author(s) 2020
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. Keywords NCS-1 · Frequenin · IDP · EF-hand · Protein folding · Order–disorder interplay
Introduction Lasse Staby and Katherine R. Kemplen contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03639-z) contains supplementary material, which is available to authorized users. * Birthe B. Kragelund [email protected] 1
Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark
2
Rigshospitalet, Finsen Laboratory, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark
3
Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark
4
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
5
Department of Biochemistry, Science Institute, University of Iceland, 107 Reykjavík, Iceland
Many studies describe the relationship between protein structure and function, with the underlying premise that the ability of a protein to perform a specific biological function is encoded in its precise three-dimensional (3D) fold [1–3]. While this view has
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