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HSPH1 Protein (Hsp110)
Introduction ... <table class="infobox infobox-protein">
HSPH1 Protein (Hsp110)
Introduction HSPH1 , also known as Hsp110 or Hsp105 , is a molecular chaperone encoded by the [HSPH1](/genes/hsph1) gene that belongs to the Hsp70 superfamily. Unlike classical Hsp70 proteins, Hsp110 functions primarily as a holdase —a chaperone that binds misfolded proteins and prevents their aggregation without actively refolding them. Hsp110 plays critical roles in protein quality control, thermotolerance, and cellular stress responses. Recent research has highlighted its importance in neurodegenerative diseases, where it contributes to the clearance of disease-specific protein aggregates [1].
Structure HSPH1 has an extended structure compared to canonical Hsp70 proteins:
N-terminal ATPase Domain (~44 kDa)
Binds and hydrolyzes ATP
Regulates substrate binding
Contains the characteristic Hsp70 ATPase fold
C-terminal Substrate-binding Domain (~50 kDa)
Larger than typical Hsp70 SBD
Contains the EEVD C-terminal motif
Functions as a high-capacity holdase
Extended Interdomain Linker
Unique to Hsp110 family
Enables flexibility in substrate interactions
Key Structural Features
Forms homodimers
Can form larger oligomers
Contains multiple phosphorylation sites
Normal Function
Protein Holdase Activity Hsp110's primary function is to bind and hold misfolded proteins:
Aggregation prevention : Sequesters hydrophobic polypeptidesSubstrate delivery : Hands off substrates to other chaperonesATP-dependent cycling : Uses ATP hydrolysis for substrate releaseProtein Refolding Working with Hsp70 and Hsp40:
Cooperative refolding : Hsp110-Hsp70-Hsp40 complexERAD function : Involved in endoplasmic reticulum-associated degradationProteasome delivery : Directs substrates to the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system)Thermotolerance Critical for cellular survival under heat stress:
Heat shock response : Major effector of thermotoleranceProtein stabilization : Protects essential proteins during heat shockRecovery function : Aids in post-stress recoveryAutophagy Regulation Hsp110 is involved in [autophagy](/entities/autophagy):
Aggrephagy : Selective autophagy of protein aggregatesChaperone-mediated autophagy : Can participate in CMAMitophagy : Quality control of mitochondriaRole in Neurodegeneration
Alzheimer's Disease Hsp110 has multiple protective roles in AD:
Amyloid-β handling :
Binds to [Aβ](/proteins/amyloid-beta) oligomers and fibrils [2]
Prevents Aβ aggregation
May facilitate Aβ clearance
[Tau](/proteins/tau) pathology :
Interacts with hyperphosphorylated tau
Can facilitate tau clearance via autophagy
Protects against tau-induced toxicity
Neuronal survival :
Maintains protein homeostasis
Anti-apoptotic functions
Protects against proteotoxic stress
Parkinson's Disease Hsp110 is particularly relevant to PD:
[α-Synuclein](/proteins/alpha-synuclein) management :
Binds to [alpha-synuclein](/proteins/alpha-synuclein) aggregates [3]
Inhibits α-synuclein fibril formation
Facilitates aggregate clearance via autophagy
ER stress :
Modulates the [unfolded protein response](/entities/unfolded-protein-response)
Protects against ER stress-induced death
Mitochondrial quality control :
Involved in mitophagy
Protects against mitochondrial dysfunction
Amyotrophic Lateral SALS In ALS:
Handles mutant SOD1 aggregates
Involved in stress granule dynamics
Motor neuron protection
Huntington's Disease In Huntington's disease:
Binds to mutant [huntingtin](/proteins/huntingtin) [Huntingtin](/proteins/huntingtin)
Reduces polyglutamine aggregation
Therapeutic potential demonstrated in models
Therapeutic Implications Hsp110 is a promising therapeutic target:
Small Molecule Modulators
Hsp110 expression inducers
Allosteric activators of Hsp110 ATPase
Gene Therapy
AAV-mediated Hsp110 delivery
Viral vector-based approaches
Combination Therapy
Hsp110 with Hsp70 or Hsp40
Combined with autophagy enhancers
Research Findings Key research developments:
Hsp110 levels decline with aging
Genetic variants affect neurodegenerative disease risk
Hsp110-based therapies showing promise in animal models
See Also
[HSPH1 Gene](/genes/hsph1)
[HSP70 Protein Family](/proteins/hsp70-protein-family)
[HSPA1A Protein](/proteins/hspa1a)
[HSPA1B Protein](/proteins/hspa1b-protein)
[Molecular Chaperones](/mechanisms/protein-quality-control-network)
[Alzheimer's Disease Pathogenesis](/mechanisms/alzheimers-disease-pathogenesis)
[Parkinson's Disease Pathogenesis](/mechanisms/parkinsons-disease-pathogenesis)
References
[Mattoo et al., Hsp110: the thermostat of protein homeostasis (2013) (2013)](https://doi.org/10.1016/j.tcb.2013.01.005)
[Rampelt et al., Hsp110 and amyloid-beta aggregation (2012) (2012)](https://doi.org/10.1074/jbc.M112.371358)
[Ebrahimi-Fakhari et al., Hsp110 and alpha-synuclein (2013) (2013)](https://doi.org/10.1074/jbc.M113.465445)
[Unknown, Kampinga & Craig, The Hsp70 chaperone machinery (2010) (2010)](https://doi.org/10.1038/nrm2941) Show full description