Hsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches

Abstract

The maturation of hemeprotein dictates that they incorporate heme and become active, but knowledge of this essential cellular process remains incomplete. Studies on chaperon Hsp90 has revealed that it drives functional heme maturation of inducible nitric oxide synthase (iNOS), soluble guanylate cyclase (sGC) hemoglobin (Hb) and myoglobin (Mb) along with other proteins including GAPDH, while globin heme maturations also need an active sGC. In all these cases, Hsp90 interacts with the heme-free or apo-protein and then drives the heme maturation by an ATP dependent process before dissociating from the heme-replete proteins, suggesting that it is a key player in such heme-insertion processes. As the studies on globin maturation also need an active sGC, it connects the globin maturation to the NO-sGC (Nitric oxide-sGC) signal pathway, thereby constituting a novel NO-sGC-Globin axis. Since many aggressive cancer cells make Hbβ/Mb to survive, the dependence of the globin maturation of cancer cells places the NO-sGC signal pathway in a new light for therapeutic intervention. Given the ATPase function of Hsp90 in heme-maturation of client hemeproteins, Hsp90 inhibitors often cause serious side effects and this can encourage the alternate use of sGC activators/stimulators in combination with specific Hsp90 inhibitors for better therapeutic intervention.

Keywords: angiogenesis; heme; heme-free; hemeprotein; metastasis; oncoproteins.

Figure 1

Representations depicting the conformational dynamics of Hsp90 (open and closed states) brought about by its ATPase function during substrate/client protein folding.

Figure 2

(A) Structures for heme a, b and c. Heme a and c are synthesized from heme b via side chain modifications shown in red. Pyrrole rings nomenclature a, b, c and o are depicted using the Hans Fischer system. (A) Adapted from Reference [33]. (B) Representative classes of heme proteins which incorporate such hemes.

Figure 3

Representations depicting similarities in Hsp90–apo–protein interactions with respect to heme deplete/replete states of sGC (A) and iNOS (B). HCP indicates an ultimate heme carrier protein which may eventually be Hsp90.

Figure 4

(A,B) Representations depicting the role of Hsp90 in hemoglobin (Hb) and myoglobin (Mb) maturations.

Figure 5

Representations depicting the role of Hsp90 and associated co-chaperons in cancer and neurodegenerative diseases.

Figure 6

Representations depicting the potent effect of Hsp90 inhibitors on the high Hsp90 ATPase in cancer or neurodegenerative diseases and the adverse effects of these inhibitors in normal cells due to inhibition of heme-maturation of depicted proteins.