Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions
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 Zn<sup>2+</sup> can initiate IDP olig...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-04-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/9/5/168 |
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| author | Carolina Cragnell Lasse Staby Samuel Lenton Birthe B. Kragelund Marie Skepö |
| author_facet | Carolina Cragnell Lasse Staby Samuel Lenton Birthe B. Kragelund Marie Skepö |
| author_sort | Carolina Cragnell |
| collection | DOAJ |
| description | 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 Zn<sup>2+</sup> 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 Zn<sup>2+</sup>. The process is critically dependent upon interaction between Zn<sup>2+</sup> 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 Zn<sup>2+</sup> induced oligomerisation may be crucial for maintaining saliva homeostasis. |
| first_indexed | 2024-12-10T16:43:59Z |
| format | Article |
| id | doaj.art-04286d0ffadf4930b2b31b4069580a58 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-10T16:43:59Z |
| publishDate | 2019-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-04286d0ffadf4930b2b31b4069580a582022-12-22T01:41:07ZengMDPI AGBiomolecules2218-273X2019-04-019516810.3390/biom9050168biom9050168Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine InteractionsCarolina Cragnell0Lasse Staby1Samuel Lenton2Birthe B. Kragelund3Marie Skepö4Division of Theoretical Chemistry, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, SwedenStructural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, 2200 Copenhagen N, DenmarkDivision of Theoretical Chemistry, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, SwedenStructural Biology and NMR Laboratory, The Linderstrøm-Lang Centre for Protein Science and Integrative Structural Biology at University of Copenhagen (ISBUC), Department of Biology, University of Copenhagen, 2200 Copenhagen N, DenmarkDivision of Theoretical Chemistry, Department of Chemistry, Lund University, P.O. Box 124, SE-221 00 Lund, SwedenIntrinsically 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 Zn<sup>2+</sup> 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 Zn<sup>2+</sup>. The process is critically dependent upon interaction between Zn<sup>2+</sup> 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 Zn<sup>2+</sup> induced oligomerisation may be crucial for maintaining saliva homeostasis.https://www.mdpi.com/2218-273X/9/5/168Intrinsically disordered proteinsoligomerisationHistatinNMRSAXScomputer simulation |
| spellingShingle | Carolina Cragnell Lasse Staby Samuel Lenton Birthe B. Kragelund Marie Skepö Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions Biomolecules Intrinsically disordered proteins oligomerisation Histatin NMR SAXS computer simulation |
| title | Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions |
| title_full | Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions |
| title_fullStr | Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions |
| title_full_unstemmed | Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions |
| title_short | Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions |
| title_sort | dynamical oligomerisation of histidine rich intrinsically disordered proteins is regulated through zinc histidine interactions |
| topic | Intrinsically disordered proteins oligomerisation Histatin NMR SAXS computer simulation |
| url | https://www.mdpi.com/2218-273X/9/5/168 |
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