Heat Shock Protein 70 (HSPA1A)

Migration, Crosslink

📖

Heat Shock Protein 70 (HSPA1A)

active

wiki page Created: 2026-04-02T07:19:14 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-hspa1a-protein

📖 Wiki Page

protein1177 wordssynced 2026-04-02

Heat Shock Protein 70 (HSPA1A)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Heat Shock Protein 70 (HSPA1A)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">[HSP40/DNAJB1](/proteins/dnajb1-protein)</td>
<td>ATPase stimulation, substrate delivery</td>
</tr>
<tr>
<td class="label">CHIP/STUB1</td>
<td>Ubiquitin ligase, degradation</td>
</tr>
<tr>
<td class="label">BAG1</td>
<td>Nucleotide exchange, proteasome targeting</td>
</tr>
<tr>
<td class="label">BAG3</td>
<td>Autophagy targeting</td>
</tr>
<tr>
<td class="label">Hsp110/HSPA4</td>
<td>Nucleotide exchange, holdase</td>
</tr>
<tr>
<td class="label">[Tau](/proteins/tau)</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">[α-synuclein](/proteins/alpha-synuclein)</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">Huntingtin</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/age_related_diseases" style="color:#ef9a9a">AGE_RELATED_DISEASES</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-5d943bfc" style="color:#ce93d8" title="Score: 0.74">Proteostasis Enhan

...

Heat Shock Protein 70 (HSPA1A)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Heat Shock Protein 70 (HSPA1A)</th>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">[HSP40/DNAJB1](/proteins/dnajb1-protein)</td>
<td>ATPase stimulation, substrate delivery</td>
</tr>
<tr>
<td class="label">CHIP/STUB1</td>
<td>Ubiquitin ligase, degradation</td>
</tr>
<tr>
<td class="label">BAG1</td>
<td>Nucleotide exchange, proteasome targeting</td>
</tr>
<tr>
<td class="label">BAG3</td>
<td>Autophagy targeting</td>
</tr>
<tr>
<td class="label">Hsp110/HSPA4</td>
<td>Nucleotide exchange, holdase</td>
</tr>
<tr>
<td class="label">[Tau](/proteins/tau)</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">[α-synuclein](/proteins/alpha-synuclein)</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">Huntingtin</td>
<td>Substrate, prevents aggregation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/age_related_diseases" style="color:#ef9a9a">AGE_RELATED_DISEASES</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-5d943bfc" style="color:#ce93d8" title="Score: 0.74">Proteostasis Enhancement via APOE Chaper...</a><br><a href="/hypothesis/h-5dbfd3aa" style="color:#ce93d8" title="Score: 0.51">Heat Shock Protein 70 Disaggregase Ampli...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">698 edges</a></td>
</tr>
</table>

<div style="float: right; margin: 0 0 1em 1em; padding: 1em; background: #f8f9fa; border: 1px solid #ddd; border-radius: 8px; font-size: 0.9em; max-width: 300px;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">HSPA1A Protein</h3>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px 8px;"><strong>Gene</strong></td><td>[HSPA1A](/genes/hspa1a)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>UniProt ID</strong></td><td>[P0DMV8](https://www.uniprot.org/uniprot/P0DMV8)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>PDB Structures</strong></td><td>[4PO2](https://www.rcsb.org/structure/4PO2), [5E84](https://www.rcsb.org/structure/5E84)</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Molecular Weight</strong></td><td>70.0 kDa</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Amino Acids</strong></td><td>641</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Subcellular Location</strong></td><td>Cytosol, nucleus</td></tr>
<tr><td style="padding: 4px 8px;"><strong>Protein Family</strong></td><td>Hsp70 family</td></tr>
</table>
</div>

Overview

Heat Shock Protein 70 family member 1A (HSPA1A), also known as Hsp70-1 or Hsp72, is a 70 kDa molecular chaperone that plays essential roles in protein folding, quality control, and cellular stress response[@mayer2005]. Encoded by the [HSPA1A](/genes/hspa1a) gene within the major histocompatibility complex class III region on chromosome 6p21.3, HSPA1A is the stress-inducible member of the Hsp70 family that is rapidly upregulated in response to proteotoxic insults[@lindquist1988].

In the nervous system, HSPA1A protects [neurons](/entities/neurons) from protein aggregation stress by preventing misfolding, facilitating refolding of damaged proteins, and targeting irreversibly damaged proteins for degradation[@muchowski2005]. Its neuroprotective functions are particularly relevant to neurodegenerative diseases characterized by protein misfolding, including Alzheimer's disease, Parkinson's disease, and Huntington's disease[@morimoto2010].

Structure and Domain Architecture

HSPA1A consists of two major functional domains connected by a conserved linker[@zuiderweg2013]:

N-Terminal Nucleotide-Binding Domain (NBD, Residues 1-382)

ATPase activity: Binds and hydrolyzes ATP to drive conformational changes
Four subdomains (IA, IB, IIA, IIB) forming a nucleotide-binding cleft
Allosteric regulation: ATP binding reduces substrate affinity; ADP increases affinity

C-Terminal Substrate-Binding Domain (SBD, Residues 383-641)

SBDβ (residues 394-507): β-sandwich structure forming the peptide-binding groove
SBDα (residues 508-641): α-helical lid that closes over bound substrate
EEVD motif (residues 638-641): Mediates interaction with co-chaperones and CHIP ubiquitin ligase

Intervernal Linker (Residues 376-393)

Highly conserved hydrophobic segment
Transmits allosteric signals between NBD and SBD
Essential for ATPase activation upon substrate binding

Co-Chaperone Binding Sites

DnaJ/Hsp40 binding: Recruitment of J-domain proteins for ATPase stimulation
Nucleotide exchange factor binding: BAG1, BAG3, Hsp110 (nucleotide exchange)
CHIP binding: Ubiquitin ligase recruitment for degradation

Normal Function in the Nervous System

Protein Folding and Quality Control

HSPA1A maintains proteostasis through multiple mechanisms[@bukau2006]:

De novo folding: Assists folding of newly synthesized polypeptides

Refolding: Rescues partially denatured proteins following stress

Translocation: Facilitates protein transport across membranes

Assembly: Mediates assembly of multi-protein complexes

Stress Response

As a stress-inducible chaperone, HSPA1A provides rapid protection against proteotoxic stress[@akerfelt2010]:

Heat shock response activation via HSF1 transcription factor
Cytoprotective upregulation within minutes of stress exposure
Anti-apoptotic activity through multiple pathways

Synaptic Function

HSPA1A supports synaptic integrity via[@morgan2001]:

Clathrin-coated vesicle uncoating (with auxilin)
Synaptic vesicle protein folding
Neurotransmitter receptor quality control

Role in Neurodegeneration

Alzheimer's Disease

HSPA1A plays multiple protective roles in AD[@evans2006]:

Amyloid-β Pathology

Inhibits [Aβ](/proteins/amyloid-beta) aggregation: Direct binding to Aβ peptides prevents fibril formation
Reduces Aβ toxicity: Neutralizes oligomeric Aβ species
Enhances clearance: Promotes Aβ degradation via proteasome and [autophagy](/entities/autophagy)

Tau Pathology

Inhibits tau aggregation: Binds tau and prevents PHF formation[@dou2003]
Promotes tau clearance: Hsp70-CHIP complex ubiquitinates pathological tau
Blocks tau seeding: Reduces cell-to-cell transmission of tau aggregates

Parkinson's Disease

HSPA1A modulates [α-synuclein](/proteins/alpha-synuclein) pathology[@klucken2004]:

Prevents α-synuclein oligomerization and fibrillization
Dissolves pre-formed α-synuclein aggregates
Reduces α-synuclein-induced neurotoxicity

Huntington's Disease

In HD models, HSPA1A[@wacker2004]:

Suppresses [huntingtin](/proteins/huntingtin) aggregation
Delays disease onset and progression
Enhances mutant huntingtin clearance

Amyotrophic Lateral Sclerosis

HSPA1A protects against SOD1 and [TDP-43](/mechanisms/tdp-43-proteinopathy) aggregation[@okadomatsumoto2000]:

Reduces SOD1 mutant aggregation
Prevents TDP-43 cytoplasmic mislocalization
Enhances proteostasis in motor neurons

Therapeutic Targeting

Pharmacological Induction

Hsp70 inducers[@kiaei2006]:

Arimoclomol: Co-inducer amplifying stress-induced Hsp70 expression; in clinical trials for ALS and IBM
Celastrol: Natural compound activating HSF1 and inducing Hsp70
Geldanamycin derivatives: Hsp90 inhibitors causing compensatory Hsp70 induction

Direct Modulators

Hsp70 activity modulators[@rousaki2011]:

MKT-077: Rhodacycline dye derivative with Hsp70 allosteric modulation
VER-155008: ATP-competitive inhibitor (research tool)
JG-98: Allosteric inhibitor of Hsp70-BAG3 interaction

Gene Therapy

Hsp70 gene delivery[@dong2015]:

AAV-mediated Hsp70 overexpression shows neuroprotection in PD models
Potential applications in protein aggregation diseases

Combination Approaches

Synergistic strategies include[@kampinga2010]:

Hsp70 induction + proteasome enhancement
Hsp70 + autophagy activation
Multi-chaperone modulation (Hsp70 + Hsp40 + Hsp110)

Protein-Protein Interactions

Summary

HSPA1A is a stress-inducible molecular chaperone that serves as a critical component of the cellular proteostasis network. Its ability to prevent protein aggregation, refold damaged proteins, and target irreversibly damaged proteins for degradation makes it a promising therapeutic target for neurodegenerative diseases characterized by protein misfolding. Current therapeutic approaches focus on pharmacological induction and direct modulation of Hsp70 activity.

Pathway & Interaction Diagram

Interactive diagram showing HSPA1A key relationships in the SciDEX knowledge graph (15 connections shown).

Mermaid diagram (expand to render)

External Links

[UniProt: P0DMV8](https://www.uniprot.org/uniprot/P0DMV8)
[NCBI Gene: 3303](https://www.ncbi.nlm.nih.gov/gene/3303)
[InterPro: IPR013126](https://www.ebi.ac.uk/interpro/entry/IPR013126/)

References

[Mayer MP, Bukau B, Hsp70 chaperones: cellular functions and molecular mechanism (2005)](https://doi.org/10.1007/s00018-004-4464-6)

[Lindquist S, Craig EA, The heat-shock proteins (1988)](https://doi.org/10.1146/annurev.ge.22.120188.003215)

[Muchowski PJ, Wacker JL, Modulation of neurodegeneration by molecular chaperones (2005)](https://doi.org/10.1038/nrn1587)

[Morimoto RI, Proteotoxic stress and the aging proteome (2010)](https://doi.org/10.1038/nrm2923)

[Zuiderweg ER, Bertelsen EB, Rousaki A, et al, Allostery in the Hsp70 chaperone proteins (2013)](https://doi.org/10.1007/128_2011_307)

[Bukau B, Weissman J, Horwich A, Molecular chaperones and protein quality control (2006)](https://doi.org/10.1016/j.cell.2006.05.014)

[Akerfelt M, Morimoto RI, Sistonen L, Heat shock factors: integrators of cell stress, development and lifespan (2010)](https://doi.org/10.1038/nrm2938)

[Morgan JR, Zhao X, Womack M, et al, A role for the chaperone protein Hsp70 in the regulation of synaptic vesicle recycling (2001)](https://doi.org/10.1523/JNEUROSCI.21-01-00018.2001)

[Evans CG, Wisén S, Gestwicki JE, Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro (2006)](https://doi.org/10.1074/jbc.M606192200)

[Dou F, Netzer WJ, Tanemura K, et al, Chaperones increase association of tau protein with microtubules (2003)](https://doi.org/10.1073/pnas.242720499)

[Klucken J, Shin Y, Masliah E, et al, Hsp70 reduces α-synuclein aggregation and toxicity (2004)](https://doi.org/10.1074/jbc.M400255200)

[Wacker JL, Zareie MH, Fong H, et al, Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers (2004)](https://doi.org/10.1038/nsmb860)

[Okado-Matsumoto A, Myint T, Fujii J, Taniguchi N, Chick glutathione peroxidase-1 is a stress-inducible enzyme (2000)](https://doi.org/10.1093/oxfordjournals.jbchem.a022617)

[Kiaei M, Kipani K, Petri S, et al, Arimoclomol prolongs survival in a transgenic animal model of amyotrophic lateral sclerosis (2006)](https://doi.org/10.1080/14660820500477528)

[Rousaki A, Miyata Y, Jinwal UK, et al, Allosteric drugs: a new strategy for treating protein misfolding diseases (2011)](https://doi.org/10.1016/j.sbi.2011.09.007)

[Dong X, Yao J, Liu C, et al, Hsp70 promotes Aβ degradation via LAMP2A-mediated lysosomal degradation (2015)](https://doi.org/10.1007/s12031-015-0540-5)

[Kampinga HH, Craig EA, The HSP70 chaperone machinery: J proteins as drivers of functional specificity (2010)](https://doi.org/10.1038/nrm2941)

📖 View canonical wiki page →

Related Entities

HSPA1APROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-hspa1a-protein
kg_node_id	HSPA1APROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-65bdcf08385e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hspa1a-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

210

Outgoing

220

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

Heat Shock Protein 70 (HSPA1A)

Heat Shock Protein 70 (HSPA1A)

Heat Shock Protein 70 (HSPA1A)

Overview

Structure and Domain Architecture

N-Terminal Nucleotide-Binding Domain (NBD, Residues 1-382)

C-Terminal Substrate-Binding Domain (SBD, Residues 383-641)

Intervernal Linker (Residues 376-393)

Co-Chaperone Binding Sites

Normal Function in the Nervous System

Protein Folding and Quality Control

Stress Response

Synaptic Function

Role in Neurodegeneration

Alzheimer's Disease

Amyloid-β Pathology

Tau Pathology

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis

Therapeutic Targeting

Pharmacological Induction

Direct Modulators

Gene Therapy

Combination Approaches

Protein-Protein Interactions

Summary

Pathway & Interaction Diagram

See Also

External Links

References

💬 Discussion