Order out of Disorder: Working Cycle of an Intrinsically Unfolded Chaperone

By Dana Reichmann, Ying Xu, Claudia M. Cremers, M. Ilbert, Roni Mittelman, M. Fitzgerald, Ursula Jakob. 2012

130 citations recorded by the source corpus.

SUMMARY The redox-regulated chaperone Hsp33 protects organisms against oxidative stress that leads to protein unfolding. Activation of Hsp33 is triggered by the oxidative unfolding of its own redox-sensor domain, making Hsp33 a member of a recently discovered class of chaperones that require partial unfolding for full chaperone activity. Here we address the long-standing question of how chaperones recognize client proteins. We show that Hsp33 uses its own intrinsically disordered regions to discriminate between unfolded and partially structured folding intermediates. Binding to secondary structure elements in client proteins stabilizes Hsp33’s intrinsically disordered regions, and this stabilization appears to mediate Hsp33’s high affinity for structured folding intermediates. Return to nonstress conditions reduces Hsp33’s disulfide bonds, which then significantly destabilizes the bound client proteins and in doing so converts them into less-structured, folding-competent client proteins of ATP-dependent foldases. We propose a model in which energy-independent chaperones use internal order-to-disorder transitions to control substrate binding and release.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding (2018, background): “This leads to the un-folding of the zinc-binding domain, exposing the substrate binding surface of the chaperone that is necessary for its activity (45).”
Analyzing Protein Disorder with IUPred2A (2020, background): “This leads to the release of the bound metal ion, and to the unfolding of the zinc-binding domain, exposing the substrate-binding surface that is required for the chaperone activity (Reichmann et al., 2012).”
Genome‐scale prediction of proteins with long intrinsically disordered regions (2014, background): “…synthases, endonucleases and exonucleases, and involvement in activity of heat shock proteins, which was recently studied by Reichmann et al .80 All considered individual functions and processes, including those that are and are not significantly enriched, were aggregated to the second…”
The roles of conditional disorder in redox proteins (2013, methodology): “These experiments showed that Hsp33’s linker region selectively binds to partially structured substrates, using them as a scaffold to refold the linker region and increasing complex stability [32 ].”