HSP90 (Heat Shock Protein 90, encoded by [HSP90AA1](/genes/hsp90aa1)) is a abundant molecular chaperone essential for cellular proteostasis. As a key component of the protein folding machinery, HSP90 stabilizes numerous client proteins involved in signaling, transcription, and cell survival. In the nervous system, HSP90 is particularly important for maintaining neuronal health and protecting against neurodegeneration.
HSP90 is unique among chaperones in that it preferentially targets signaling proteins and mutated proteins that are close to their native conformation. This makes it critically important for neurodegenerative diseases, where mutant proteins (such as mutant SOD1 in ALS, mutant [tau](/proteins/tau) in AD) are client proteins. HSP90 inhibitors are being actively investigated for cancer therapy and have shown promise in neurodegenerative disease models.
Structure
HSP90 has a distinctive multi-domain structure:
N-terminal ATPase domain (~25 kDa): Binds and hydrolyzes ATP, the energy source for chaperone activity
Middle domain (~35 kDa): Client protein binding site, connects ATP hydrolysis to substrate binding
C-terminal dimerization domain (~12 kDa): Mediates HSP90 dimerization, required for function
EEVD motif: Conserved C-terminal sequence for co-chaperone binding
The dimeric structure of HSP90 is essential for its function. The ATPase cycle involves:
Open conformation: ATP binding induces dimer closure
Closed conformation: ATP hydrolysis triggers client protein folding
ADP release: Returns to open state for client release
Normal Function in the Nervous System
Chaperone Function
HSP90 maintains proteostasis through:
Client protein maturation: Helps fold signaling proteins, steroid receptors, kinases
Complex assembly: Facilitates formation of multi-protein complexes
Quality control: Targets misfolded proteins for degradation
Stress protection: Rapidly upregulated under various stresses
Neuronal Functions
In neurons, HSP90:
Axonal transport: Associated with transport machinery
Synaptic function: Regulates synaptic protein complexes