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

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer5199
TidsskriftScientific Reports
Vol/bind8
Antal sider15
ISSN2045-2322
DOI
StatusUdgivet - 2018

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Citationsformater

Söderberg, C. A. G., 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, 8, [5199]. https://doi.org/10.1038/s41598-018-23035-9