Modular construction of the heat-shock protein 90 (HSP90) network.

<p>Three modules form the whole network: HSF1 trimer formation, phosphorylation-dephosphorylation reactions of the HSP90:HSF1 trimer complex, and the conversion of an open to a closed HSP90 protein conformation. Module 1, shown in red, is the trimer formation of HSF1. Inactive HSF1 monomer sequestered by the closed conformation of HSP90 () forms a complex, . Stress releases the inactive HSF1 monomer from the complex, and turns it into an active form, HSF1S, to produce a dimer (HSF12S) slowly, but a trimer (HSF13S) rapidly. The trimer binds to the heat-shock element (HSE) to form a complex, HH, but it is incompetent to transcribe the hsp90 gene, unless strongly phosphorylated. Module 2, shown in blue, consists of the PdP reactions of the complex HH. The trimer HSF1S in the HH complex is hyper-phosphorylated by the kinase (MK3) and dephosphorylated by the phosphatase PP5, a co-chaperone. Hyper-phosphorylated HH () is competent to transcribe the hsp90 gene to produce , which in turn translates into an open conformation of the HSP90 protein by series of steps. Module 3, shown in black, represents the formation of HSP90 closed conformation in which the open form of binds to adenosine triphosphate (ATP), and converts it to conformation through two step wise intermediate conformations (). The fate of the closed form, which is competent to bind the substrate or the client proteins is three-fold: it (i) can shed the ATP to attain an open conformer, (ii) can bind to HSF1 monomer to negatively regulate its own production, finally (iii) can degrade to form a dead product, .