Abstract
Bacteria as unicellular organisms are most directly exposed to changes in environmental growth conditions like temperature increase. Severe heat stress causes massive protein misfolding and aggregation resulting in loss of essential proteins. To ensure survival and rapid growth resume during recovery periods bacteria are equipped with cellular disaggregases, which solubilize and reactivate aggregated proteins. These disaggregases are members of the Hsp100/AAA+ protein family, utilizing the energy derived from ATP hydrolysis to extract misfolded proteins from aggregates via a threading activity. Here, we describe the two best characterized bacterial Hsp100/AAA+ disaggregases, ClpB and ClpG, and compare their mechanisms and regulatory modes. The widespread ClpB disaggregase requires cooperation with an Hsp70 partner chaperone, which targets ClpB to protein aggregates. Furthermore, Hsp70 activates ClpB by shifting positions of regulatory ClpB M-domains from a repressed to a derepressed state. ClpB activity remains tightly controlled during the disaggregation process and high ClpB activity states are likely restricted to initial substrate engagement. The recently identified ClpG (ClpK) disaggregase functions autonomously and its activity is primarily controlled by substrate interaction. ClpG provides enhanced heat resistance to selected bacteria including pathogens by acting as a more powerful disaggregase. This disaggregase expansion reflects an adaption of bacteria to extreme temperatures experienced during thermal based sterilization procedures applied in food industry and medicine. Genes encoding for ClpG are transmissible by horizontal transfer, allowing for rapid spreading of extreme bacterial heat resistance and posing a threat to modern food production.
Highlights
Environmental stress conditions like heat shock that cause enhanced misfolding of newly synthesized or preexisting proteins trigger stress responses, Functions and Mechanisms of Protein Disaggregases which lead to an increase in the levels of Protein quality control (PQC) components, thereby enabling cells to deal with the increased load for the proteostasis network
Protein aggregates are deposited at the cell poles of bacteria involving a passive process that is mainly driven by nucleoid occlusion (Winkler et al, 2010)
Why is protein aggregation becoming a critical factor for bacterial survival during severe heat stress? The analysis of heat-induced protein aggregates revealed the presence of various proteins playing essential roles in diverse housekeeping processes including cell division (e.g., FtsZ), transcription (e.g., RNA polymerase) and translation (e.g., EF-G) (Mogk et al, 1999; Pu et al, 2019)
Summary
The bacterial disaggregases ClpB and ClpG are members of the Hsp100/AAA+ protein family. We focus on the structures of the ClpB disaggregase and its yeast homolog Hsp104, which both share common features with other AAA+ proteins, pointing to a conserved mechanism of ATP hydrolysis and substrate threading (Deville et al, 2017, 2019; Gates et al, 2017; Yu et al, 2018; Rizo et al, 2019). The coating of the aggregate surface by DnaK provides specificity for reactivating ClpB and prevents binding of Hsp100/AAA+ proteins (e.g., ClpA/ClpC) that cooperate with peptidases (e.g., ClpP) (Haslberger et al, 2008).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
