Figure 1.

Regulation of the Hsp90 chaperone cycle by co-chaperones. Progression of client proteins through the Hsp90-mediated chaperone folding pathway is regulated by co-chaperones, which act at defined stages in the cycle. Co-chaperones may regulate Hsp90 association with clients, ATPase activity, conformational changes, and post-translational modifications. When inactive, Hsp90 is constitutively dimerized at the C-terminus but not the N-terminus. Entry of client proteins is facilitated by co-chaperones including the Hsp70/Hsp90 organizing protein Hop, which regulates transfer of clients from Hsp70 by binding simultaneously to Hsp70 and Hsp90, to form the intermediate complexes. Hop is conserved in Plasmodium falciparum (PfHop, PF3D7_1434300). Kinase clients require the kinase-specific co-chaperone Cdc37; however, a Cdc37-encoding gene has not been identified in the P. falciparum genome. On ATP binding, Hsp90 undergoes N-terminal dimerization, and the client protein associates with the middle domain of Hsp90. Bindings of other co-chaperones, including peptidyl-prolyl cis–trans isomerases (PPIase) and protein phosphatase 5 (PP5), associate to form the asymmetric Hsp90 complexes. The P. falciparum genome encodes a PP5 isoform (PfPP5, PF3D7_1355500) and multiple PPIase isoforms (PfFKBP35, PF3D7_1247400; PfCns1, PF3D7_1108900; and PfCyp40, PF3D7_1111800). These co-chaperones regulate the post-translational modification and maturation of Hsp90 complexes. Early co-chaperones subsequently dissociate from the complex to be replaced by p23, which stabilizes the late closed Hsp90 complex and the client within the complex, and inhibits ATPase activity. Two homologs of p23 are encoded in the P. falciparum genome (Pfp23A, PF3D7_1453700; and Pf23B, PF3D7_0927000). ATP hydrolysis is stimulated by binding of Aha1, resulting in release of the client protein and a return of Hsp90 to the inactive conformation. The P. falciparum genome encodes a single Aha1 isoform (PfAha1, PF3D7_0306200). Image created with BioRender.com.