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

Christopher A.G. Söderberg*, Cecilia Månsson, Katja Bernfur, Gudrun Rutsdottir, Johan Härmark, Sreekanth Rajan, Salam Al-Karadaghi, Morten Rasmussen, Peter Höjrup, Hans Hebert, Cecilia Emanuelsson

*Corresponding author for this work

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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 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.

Original languageEnglish
Article number5199
JournalScientific Reports
Volume8
Number of pages15
ISSN2045-2322
DOIs
Publication statusPublished - 2018

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Peptides
Isotopes
Lysine
Electron Microscopy
X-Rays
Proteins

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Söderberg, Christopher A.G. ; Månsson, Cecilia ; Bernfur, Katja ; Rutsdottir, Gudrun ; Härmark, Johan ; Rajan, Sreekanth ; Al-Karadaghi, Salam ; Rasmussen, Morten ; Höjrup, Peter ; Hebert, Hans ; Emanuelsson, Cecilia. / Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface. In: Scientific Reports. 2018 ; Vol. 8.
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title = "Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface",
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 of oligomers with a varying number of subunits according to small-angle X-ray scattering (SAXS). Elongated particles (160 × 120 {\AA}) were detected by electron microscopy and single particle reconstruction resulted in a density map of 20 {\AA} 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.",
author = "S{\"o}derberg, {Christopher A.G.} and Cecilia M{\aa}nsson and Katja Bernfur and Gudrun Rutsdottir and Johan H{\"a}rmark and Sreekanth Rajan and Salam Al-Karadaghi and Morten Rasmussen and Peter H{\"o}jrup and Hans Hebert and Cecilia Emanuelsson",
year = "2018",
doi = "10.1038/s41598-018-23035-9",
language = "English",
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Söderberg, CAG, Månsson, C, Bernfur, K, Rutsdottir, G, Härmark, J, Rajan, S, Al-Karadaghi, S, Rasmussen, M, Höjrup, P, Hebert, H & Emanuelsson, C 2018, 'Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface', Scientific Reports, vol. 8, 5199. https://doi.org/10.1038/s41598-018-23035-9

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.; Månsson, Cecilia; Bernfur, Katja; Rutsdottir, Gudrun; Härmark, Johan; Rajan, Sreekanth; Al-Karadaghi, Salam; Rasmussen, Morten; Höjrup, Peter; Hebert, Hans; Emanuelsson, Cecilia.

In: Scientific Reports, Vol. 8, 5199, 2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Structural modelling of the DNAJB6 oligomeric chaperone shows a peptide-binding cleft lined with conserved S/T-residues at the dimer interface

AU - Söderberg, Christopher A.G.

AU - Månsson, Cecilia

AU - Bernfur, Katja

AU - Rutsdottir, Gudrun

AU - Härmark, Johan

AU - Rajan, Sreekanth

AU - Al-Karadaghi, Salam

AU - Rasmussen, Morten

AU - Höjrup, Peter

AU - Hebert, Hans

AU - Emanuelsson, Cecilia

PY - 2018

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N2 - 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.

AB - 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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DO - 10.1038/s41598-018-23035-9

M3 - Journal article

C2 - 29581438

AN - SCOPUS:85044502155

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 5199

ER -