Hsp90—From signal transduction to cell transformation

Abstract

The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation

“…This suggests a role for Hop in Hsp90-mediated inhibition of invasion through extracellular interactions. Hop acts as a co-chaperone in the Hsp90 chaperone cycle stabilising and activating a wide array of client proteins [30]. Having demonstrated that Hop knockdown resulted in decreased invasion through extracellular interaction with Hsp90 and MMP-2, we investigated whether siRNA knockdown of Hop could affect Hsp90-mediated client protein expression.…”

Inhibition of infectious bursal disease virus infection by artificial microRNAs targeting chicken heat-shock protein 90

“…To facilitate effective miRNA selection, we constructed reporter vectors for co-transfection with the miRNA vectors, by which effective miRNAs could be screened easily according to reduction of EGFPpositive cell numbers in the co-transfected cell cultures. Among seven candidate miRNAs tested using the reporter assay, five of them were shown to have significant inhibitory effects on cHsp90a or cHsp90b transcription, confirming the high reliability of the web-based siRNAdesign tool and our miRNA-expression system.The claim that cHsp90 is a functional component of the cellular receptor complex for IBDV binding is drawn from indirect evidence using an anti-human Hsp90a mAb (Lin et al, 2007); this cannot rule out the possibility of crossreactivity between cHsp90a and cHsp90b, as the two proteins are 85 % identical (Brown et al, 2007). Our stable transfection experiments showed that the anti-cHsp90a…”

Heat Shock Proteins in Cardiovascular Stress

“…However, HSP90 is not capable of independent functionality as a protein chaperone, but requires the augmentation of its co-chaperones. HSP90 is crucial in signal transduction to transformation to genetic capacitance and infl uences a wide array of cellular events (Brown et al 2007). …”