HSP90

Heat shock protein 90 (HSP90) functions as an ATP-dependent molecular chaperone that regulates the folding, stability, and activity of numerous signaling proteins^[1][2]. HSP90 participates in essential cellular processes, including signal transduction, cell cycle control, stress management, and protein quality control, and operates in coordination with HSP70, HSP40, and co-chaperones such as Hop and p23 to ensure proper client maturation^[3][4][5][6]. The cytosolic isoforms, HSP90α and HSP90β, exhibit distinct biological roles: HSP90β is constitutively expressed and critical for cellular survival, whereas HSP90α is stress-inducible and supports extracellular functions under pathological conditions^[7][8][9]. Mechanistically, HSP90 interacts with clients by recognizing hydrophobic residues across multiple domains, and its chaperone activity is fine-tuned by tetratricopeptide repeat (TPR) domain-containing co-chaperones and post-translational modifications^[3][2][10]. In disease models, HSP90 supports oncogenic signaling, promotes metastasis via extracellular HSP90α-mediated MMP-2 activation, and regulates protein homeostasis in neurodegenerative and renal stress conditions^{[11][12][13][9]}. Compared with HSP90α, HSP90β shows higher structural stability, distinct thermal unfolding properties, and isoform-specific interactions with selective clients, which are exploited in experimental pharmacological interventions^[8][9][14]. Selective inhibitors targeting HSP90β demonstrate therapeutic potential by modulating protein folding and proteostasis while minimizing compensatory HSP90α upregulation and extracellular secretion^[9][15]. Overall, understanding isoform-specific mechanisms and co-chaperone interactions facilitates the rational design of HSP90-targeted research and therapeutic strategies^[16][7].

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