HSPH1 Protein

<table class="infobox infobox-protein">
<tr><th class="infobox-header" colspan="2">HSPH1 Protein</th></tr>
<tr><td class="label">Protein Name</td><td>Hsp110 (Heat Shock Protein 105)</td></tr>
<tr><td class="label">Gene</td><td>[HSPH1](/genes/hsph1)</td></tr>
<tr><td class="label">UniProt</td><td><a href="https://www.uniprot.org/uniprot/Q92598" target="_blank">Q92598</a></td></tr>
<tr><td class="label">Molecular Weight</td><td>~97 kDa</td></tr>
<tr><td class="label">Subcellular Localization</td><td>Cytoplasm, Nucleus</td></tr>
<tr><td class="label">Protein Family</td><td>Hsp70 superfamily (Hsp110 family)</td></tr>
<tr><td class="label">Aliases</td><td>HSP105, Hsp110, HSPH1</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/gastric-cancer" style="color:#ef9a9a">Gastric Cancer</a>, <a href="/wiki/lymphoma" style="color:#ef9a9a">Lymphoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">47 edges</a></td>
</tr>
</table>

HSPH1 Protein (Hsp110)

Introduction

<table class="infobox infobox-protein">
<tr><th class="infobox-header" colspan="2">HSPH1 Protein</th></tr>
<tr><td class="label">Protein Name</td><td>Hsp110 (Heat Shock Protein 105)</td></tr>
<tr><td class="label">Gene</td><td>[HSPH1](/genes/hsph1)</td></tr>
<tr><td class="label">UniProt</td><td><a href="https://www.uniprot.org/uniprot/Q92598" target="_blank">Q92598</a></td></tr>
<tr><td class="label">Molecular Weight</td><td>~97 kDa</td></tr>
<tr><td class="label">Subcellular Localization</td><td>Cytoplasm, Nucleus</td></tr>
<tr><td class="label">Protein Family</td><td>Hsp70 superfamily (Hsp110 family)</td></tr>
<tr><td class="label">Aliases</td><td>HSP105, Hsp110, HSPH1</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/gastric-cancer" style="color:#ef9a9a">Gastric Cancer</a>, <a href="/wiki/lymphoma" style="color:#ef9a9a">Lymphoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">47 edges</a></td>
</tr>
</table>

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 polypeptides
• Substrate delivery: Hands off substrates to other chaperones
• ATP-dependent cycling: Uses ATP hydrolysis for substrate release

Protein Refolding

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](/mechanisms/ubiquitin-proteasome-system)

Thermotolerance

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

Autophagy Regulation

Hsp110 is involved in [autophagy](/entities/autophagy):

• Aggrephagy: Selective autophagy of protein aggregates
• Chaperone-mediated autophagy: Can participate in CMA
• Mitophagy: Quality control of mitochondria

Role 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

• Interacts with hyperphosphorylated tau
• Can facilitate tau clearance via autophagy
• Protects against tau-induced toxicity

• 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

• Modulates the [unfolded protein response](/entities/unfolded-protein-response)
• Protects against ER stress-induced death

• 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