8.A.163. The HSP90/CDC37 (HSP90/CDC37) Family
The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication (Heider et al. 2021). Cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), is a co-chaperone that specifically determines chaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90. Among the multiple transmembrane protein clients of CRBN-AHA1-HSP90 revealed by cell surface proteomics, is the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity in multiple myeloma (MM) and present an Anticalin-based CD98hc radiopharmaceutical for MM radio-theranostics. These data establish the CRBN-AHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and nominate CD98hc and LAT1 as attractive diagnostic and therapeutic targets in MM (Heider et al. 2021). AUY922, an Hsp90 inhibitor, induces retinal toxicity through attenuating TRPM1 (Shen et al. 2021).
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HSP90AB1 (HSP90B, HSPC2, HSPCB) of 724 aas, which forms a complex with the cochaparone protein, CDC37 (378 aas) and AHA1 (338 aas), in the cytoplasm. HSP90 is an ATP-driven chaparone. It promotes the maturation, structural maintenance and proper regulation of specific target proteins including integral membrane proteins and transporters involved, for instance, in cell cycle control, signal transduction and transport. It undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. It also interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function (Chadli et al. 2006, Retzlaff et al. 2009). In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state (Richter et al. 2008). The chaparone complex interacts with cereblon (CDBN; TC# 8.A.162.1.1) which determines HSP90 activity toward transmembrane proteins (Heider et al. 2021).
HSP90/CDC37/AHA1 of Homo sapiens
Hsp90 molecular chaparone homologue Hsp90 in S. cerevisiae of 644 aas
Hsp90 homologue in Streptomyces albus
Molecular chaparone protein, Hsp90 homologue, of 634 aas
Hsp90 of Pseudomonas aeruginosa