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Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface

Söderberg, Christopher A.G. LU ; Månsson, Cecilia LU ; Bernfur, Katja LU ; Rutsdottir, Gudrun LU ; Härmark, Johan; Rajan, Sreekanth LU ; Al-Karadaghi, Salam LU ; Rasmussen, Morten; Höjrup, Peter and Hebert, Hans LU , et al. (2018) In Scientific Reports 8(1).
Abstract

The remarkably efficient suppression of amyloid fibril formation by the DNAJB6 chaperone is dependent on a set of conserved S/T-residues and an oligomeric structure, features unusual among DNAJ chaperones. We explored the structure of DNAJB6 using a combination of structural methods. Lysine-specific crosslinking mass spectrometry provided distance constraints to select a homology model of the DNAJB6 monomer, which was subsequently used in crosslink-assisted docking to generate a dimer model. A peptide-binding cleft lined with S/T-residues is formed at the monomer-monomer interface. Mixed isotope crosslinking showed that the oligomers are dynamic entities that exchange subunits. The purified protein is well folded, soluble and composed... (More)

The remarkably efficient suppression of amyloid fibril formation by the DNAJB6 chaperone is dependent on a set of conserved S/T-residues and an oligomeric structure, features unusual among DNAJ chaperones. We explored the structure of DNAJB6 using a combination of structural methods. Lysine-specific crosslinking mass spectrometry provided distance constraints to select a homology model of the DNAJB6 monomer, which was subsequently used in crosslink-assisted docking to generate a dimer model. A peptide-binding cleft lined with S/T-residues is formed at the monomer-monomer interface. Mixed isotope crosslinking showed that the oligomers are dynamic entities that exchange subunits. The purified protein is well folded, soluble and composed of oligomers with a varying number of subunits according to small-angle X-ray scattering (SAXS). Elongated particles (160 × 120 Å) were detected by electron microscopy and single particle reconstruction resulted in a density map of 20 Å resolution into which the DNAJB6 dimers fit. The structure of the oligomer and the S/T-rich region is of great importance for the understanding of the function of DNAJB6 and how it can bind aggregation-prone peptides and prevent amyloid diseases.

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Scientific Reports
volume
8
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85044502155
ISSN
2045-2322
DOI
10.1038/s41598-018-23035-9
language
English
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yes
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a0d3e02b-d5bc-4616-9bd2-2058e699acb4
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2018-04-10 09:42:34
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2018-08-26 05:02:54
@article{a0d3e02b-d5bc-4616-9bd2-2058e699acb4,
  abstract     = {<p>The remarkably efficient suppression of amyloid fibril formation by the DNAJB6 chaperone is dependent on a set of conserved S/T-residues and an oligomeric structure, features unusual among DNAJ chaperones. We explored the structure of DNAJB6 using a combination of structural methods. Lysine-specific crosslinking mass spectrometry provided distance constraints to select a homology model of the DNAJB6 monomer, which was subsequently used in crosslink-assisted docking to generate a dimer model. A peptide-binding cleft lined with S/T-residues is formed at the monomer-monomer interface. Mixed isotope crosslinking showed that the oligomers are dynamic entities that exchange subunits. The purified protein is well folded, soluble and composed of oligomers with a varying number of subunits according to small-angle X-ray scattering (SAXS). Elongated particles (160 × 120 Å) were detected by electron microscopy and single particle reconstruction resulted in a density map of 20 Å resolution into which the DNAJB6 dimers fit. The structure of the oligomer and the S/T-rich region is of great importance for the understanding of the function of DNAJB6 and how it can bind aggregation-prone peptides and prevent amyloid diseases.</p>},
  articleno    = {5199},
  author       = {Söderberg, Christopher A.G. and Månsson, Cecilia and Bernfur, Katja and Rutsdottir, Gudrun and Härmark, Johan and Rajan, Sreekanth and Al-Karadaghi, Salam and Rasmussen, Morten and Höjrup, Peter and Hebert, Hans and Emanuelsson, Cecilia},
  issn         = {2045-2322},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface},
  url          = {http://dx.doi.org/10.1038/s41598-018-23035-9},
  volume       = {8},
  year         = {2018},
}