Hsp70s are a diverse family of chaperones that execute a variety of proteostatic and protein processing reactions. They include the eukaryotic Hsp110s, which function as nucleotide exchange factors for other Hsp70s and thereby regulate association of Hsp70s with their protein substrates. Hsp110s also display protein substrate‐binding domains that shield misfolded proteins from aggregation. Through these activities, Hsp110s contribute to a range of protein processing reactions including recovery from stresses such as heat or ischemic shocks, protein aggregation inhibition and aggregate solubilisation, prion propagation and assembly/disassembly of polymeric protein complexes. These functions result in Hsp110s, contributing both positively and negatively to multiple disease etiologies. Positively, because they inhibit degenerative diseases associated with protein aggregation and negatively because these same activities stimulate cancer proliferation and allow cancer cells to survive the stress of radiologic and chemotherapies. Consequently, Hsp110s are targets of therapeutic approaches that aim to both stimulate and inhibit their activities.
Key Concepts
Hsp70s are proteins that bind other, often misfolded, proteins so as to either inhibit interactions made by those proteins, break up protein:protein associations or move proteins between cellular compartments.
ATP binding causes Hsp70s to release their bound protein substrates, while ADP causes them to hold tightly to those substrates.
Hsp110s cause Hsp70s to release ADP so that they can then bind ATP, which then causes the Hsp70 to release its bound protein substrate. In this way, Hsp110s regulate Hsp70:substrate associations.
The crystal structure of an Hsp110:Hsp70 complex reveals how Hsp110 induces nucleotide exchange and why it is so effective at doing so.
Hsp110s are also able to bind directly to misfolded proteins to block their aggregation, but cannot unfold and refold these proteins as canonical Hsp70s can.
Hsp110s strongly stimulate the ability of canonical Hsp70s to solubilise protein aggregates
in vitro
.
Hsp110s are induced by stresses such as heat or ischaemic shocks and assist cellular recovery from such traumas.
Hsp110s inhibit protein aggregation and help solubilise protein aggregates
in vivo
.
Hsp110 roles in aggregate solubilisation and aggregation inhibition makes stimulation of their activities a goal for treatment of degenerative diseases associated with protein aggregation.
Hsp110 activities support cancer cell growth and therapeutic resistance and make Hsp110 inhibition a goal in cancer treatment.