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| Protein Name | Hsp110 (Heat Shock Protein 105) |
| Gene | [HSPH1](/genes/hsph1) |
| UniProt | Q92598 |
| Molecular Weight | ~97 kDa |
| Subcellular Localization | Cytoplasm, Nucleus |
| Protein Family | Hsp70 superfamily (Hsp110 family) |
| Aliases | HSP105, Hsp110, HSPH1 |
HSPH1, also known as Hsp110 or Hsp105, is a molecular chaperone encoded by the 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].
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
- Forms homodimers
- Can form larger oligomers
- Contains multiple phosphorylation sites
Hsp110's primary function is to bind and hold misfolded proteins:
- Aggregation prevention: Sequesters hydrophobic polypeptides
- Substrate delivery: Hands off substrates to other chaperones
- ATP-dependent cycling: Uses ATP hydrolysis for substrate release
Working with Hsp70 and Hsp40:
- Cooperative refolding: Hsp110-Hsp70-Hsp40 complex
- ERAD function: Involved in endoplasmic reticulum-associated degradation
- Proteasome delivery: Directs substrates to the ubiquitin-proteasome system
Critical for cellular survival under heat stress:
- Heat shock response: Major effector of thermotolerance
- Protein stabilization: Protects essential proteins during heat shock
- Recovery function: Aids in post-stress recovery
Hsp110 is involved in autophagy:
- Aggrephagy: Selective autophagy of protein aggregates
- Chaperone-mediated autophagy: Can participate in CMA
- Mitophagy: Quality control of mitochondria
Hsp110 has multiple protective roles in AD:
Amyloid-β handling:
- Binds to Aβ oligomers and fibrils [2]
- Prevents Aβ aggregation
- May facilitate Aβ clearance
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
Hsp110 is particularly relevant to PD:
α-Synuclein management:
- Binds to alpha-synuclein aggregates [3]
- Inhibits α-synuclein fibril formation
- Facilitates aggregate clearance via autophagy
ER stress:
Mitochondrial quality control:
- Involved in mitophagy
- Protects against mitochondrial dysfunction
In ALS:
- Handles mutant SOD1 aggregates
- Involved in stress granule dynamics
- Motor neuron protection
In Huntington's disease:
- Binds to mutant huntingtin Huntingtin
- Reduces polyglutamine aggregation
- Therapeutic potential demonstrated in models
Hsp110 is a promising therapeutic target:
- Hsp110 expression inducers
- Allosteric activators of Hsp110 ATPase
- AAV-mediated Hsp110 delivery
- Viral vector-based approaches
- Hsp110 with Hsp70 or Hsp40
- Combined with autophagy enhancers
Key research developments:
- Hsp110 levels decline with aging
- Genetic variants affect neurodegenerative disease risk
- Hsp110-based therapies showing promise in animal models