Abstract
Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn2+ can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn2+. The process is critically dependent upon interaction between Zn2+ ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn2+ induced oligomerisation may be crucial for maintaining saliva homeostasis.
Highlights
It has been firmly established that intrinsically disordered proteins (IDPs) regulate many biological processes [1]
By studying five different variants of Histatin 5 (Hst5), designed to elucidate the effect of dynamic histidine coordination, we suggest a possible mechanism for oligomer formation, and we hypothesise this to be a general mechanism for oligomerisation in the presence of divalent cations of histidine rich IDPs
We have earlier shown that the form factor of Hst5 under physiological conditions can be obtained at a concentration of 1 mg/mL, and that its solution behaviour is consistent with that of an IDP [25,26]
Summary
It has been firmly established that intrinsically disordered proteins (IDPs) regulate many biological processes [1]. The functions of IDPs often involve interactions with other macromolecules [4] These interactions can be regulated through biological processes such as post-translational modification [5,6] and through interactions with other molecules including divalent metal ions such as Ni2+ , Cu2+ , and Zn2+ [7,8]. A group of intrinsically disordered phosphoproteins including casein and osteopontin interact with calcium phosphate in milk through phosphorylated residues, thereby stabilising the fluid [10,11,12,13] Another example is statherin, a saliva protein that transports calcium and magnesium to the enamel, a crucial process required to maintain the mineral phase of teeth [14,15]
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