Abstract
Protein homeostasis (proteostasis) is an essential pillar for correct cellular function. Impairments in proteostasis are encountered both in aging and in several human disease conditions. Molecular chaperones are important players for proteostasis; in particular, heat shock protein 70 (Hsp70) has an essential role in protein folding, disaggregation, and degradation. We have recently proposed a model for Hsp70 functioning as a “multiple socket”. In the model, Hsp70 provides a physical platform for the binding of client proteins, other chaperones, and cochaperones. The final fate of the client protein is dictated by the set of Hsp70 interactions that occur in a given cellular context. Obtaining structural information of the different Hsp70-based protein complexes will provide valuable knowledge to understand the functional mechanisms behind the master role of Hsp70 in proteostasis. We additionally evaluate some of the challenges for attaining high-resolution structures of such complexes.
Highlights
Protein homeostasis—the balance of protein synthesis, folding, trafficking, assembly, and degradation—is essential for correct cellular function, and cells have developed a number of strategies to control it under stress
We proposed that Hsp[70] could be playing its master role in protein homeostasis in a more passive way, namely as a “multiple socket” that provides a physical platform for the binding of client proteins and for the interaction with different chaperones and cochaperones
Hsp[90] binds client proteins through an extended interface that enables a large number of low-affinity contacts. These chaperones are assisted by several cochaperones like Hsp40s, which have an essential role in targeting substrates to Hsp[70] (Figure 1), or heat shock protein 70 (Hsp70)/Hsp90organizing protein (Hop) that facilitates the transferring of substrates from Hsp[70] to Hsp9019
Summary
Protein homeostasis (proteostasis)—the balance of protein synthesis, folding, trafficking, assembly, and degradation—is essential for correct cellular function, and cells have developed a number of strategies to control it under stress. Hsp[90] binds client proteins through an extended interface that enables a large number of low-affinity contacts These chaperones are assisted by several cochaperones like Hsp40s, which have an essential role in targeting substrates to Hsp[70] (Figure 1), or Hsp70/Hsp90organizing protein (Hop) that facilitates the transferring of substrates from Hsp[70] to Hsp9019. The Lid domain is known to have a prominent role in the binding of the specific client proteins[64], and the most C-terminal sequence of Hsp[70] is important for the binding of cochaperones such as CHIP or Hop[65,66] This implies that structural studies aiming to resolve the mechanisms of the fine-tuned Hsp[70] function should not disregard these important Hsp[70] domains. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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.
