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Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered ProteinS Is Regulated through Zinc-Histidine Interactions

Cragnell, Carolina LU ; Staby, Lasse ; Lenton, Samuel LU ; Kragelund, Birthe B. and Skepö, Marie LU orcid (2019) In Biomolecules 9(5).
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... (More)

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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
computer simulation, Histatin, Intrinsically disordered proteins, NMR, oligomerisation, SAXS
in
Biomolecules
volume
9
issue
5
article number
168
publisher
MDPI AG
external identifiers
  • scopus:85065675367
  • pmid:31052346
ISSN
2218-273X
DOI
10.3390/biom9050168
language
English
LU publication?
yes
id
f4ca92c0-a1fc-43cb-9023-6525753117da
date added to LUP
2019-05-29 08:33:21
date last changed
2025-01-09 11:50:39
@article{f4ca92c0-a1fc-43cb-9023-6525753117da,
  abstract     = {{<p>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.</p>}},
  author       = {{Cragnell, Carolina and Staby, Lasse and Lenton, Samuel and Kragelund, Birthe B. and Skepö, Marie}},
  issn         = {{2218-273X}},
  keywords     = {{computer simulation; Histatin; Intrinsically disordered proteins; NMR; oligomerisation; SAXS}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{5}},
  publisher    = {{MDPI AG}},
  series       = {{Biomolecules}},
  title        = {{Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered ProteinS Is Regulated through Zinc-Histidine Interactions}},
  url          = {{http://dx.doi.org/10.3390/biom9050168}},
  doi          = {{10.3390/biom9050168}},
  volume       = {{9}},
  year         = {{2019}},
}