Fluconazole, Cytochrome P450 inhibitor

Supplementary information

This supplementary information is collated from multiple sources and compiled automatically.

Hsp90 also known as Heat Shock Protein 90 is a molecular chaperone with a mass of about 90 kDa. It assists in the proper folding stabilization and degradation of many proteins. Hsp90 is widely expressed in the cytoplasm and the endoplasmic reticulum (ER) of eukaryotic cells and is responsible for maintaining protein homeostasis especially during stress conditions like heat shock. TDP43 or TAR DNA-binding Protein 43 has a mass of about 43 kDa and is mostly located in the nucleus although it may shuttle between the nucleus and the cytoplasm. TDP43 is involved in RNA processing such as splicing transport and stability. Both Hsp90 and TDP43 maintain functional cellular machinery.

Biological function summary

Hsp90 and TDP43 are essential in several cellular activities. Hsp90 is important for the maturation and activation of a variety of client proteins including steroid hormone receptors and kinases. It also forms a complex with co-chaperones such as Cdc37 and Hop to fulfill its functions. TDP43 regulates RNA splicing and is involved in the regulation of various RNA metabolic processes. TDP43 does not typically function as part of a complex but interacts dynamically with RNA and DNA within the nucleus.

Pathways

Hsp90 plays an important role in the cellular stress response and the proteostasis network where it ensures correct protein folding and prevents aggregation of misfolded proteins. It interacts with proteins such as Akt and Raf in pathways related to cell survival and growth. TDP43 is integral in RNA processing pathways and is linked to transcription regulation and the splicing machinery. It interacts with numerous RNA-binding proteins such as hnRNPs to mediate its biological function.

Hsp90 is associated with cancer as it stabilizes numerous oncoproteins making it a target for anticancer therapies. TDP43 on the other hand is closely linked to neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathological aggregation of TDP43 is a hallmark of these diseases. Both Hsp90 and TDP43 interact with various proteins contributing to disease pathogenesis where in neurodegenerative contexts Hsp90 inhibitors might help reduce toxic protein aggregation highlighting a connection between these chaperones and protein misfolding diseases.