HSPA1A

GeneName

HSPA1A

Summary

HSPA1A, also known as Hsp70 or HSP72, is a 70kDa heat shock protein that functions primarily as a chaperone, facilitating proper protein folding and preventing aggregation of misfolded proteins. It is expressed in various tissues and localised in multiple cellular compartments, including the cytoplasm, nucleus, mitochondria, and endoplasmic reticulum. HSPA1A plays a crucial role in the cellular response to stress, particularly heat and oxidative stress, by engaging in ATP-dependent protein refolding and disaggregation. Additionally, it is involved in the regulation of apoptotic processes and has been implicated in various signalling pathways through its interactions with other proteins and receptors.

Importance

HSPA1A is relevant to: - Cellular stress responses, including heat shock and oxidative stress, which are vital for cell survival and function - Protein homeostasis and quality control mechanisms, as it assists in the refolding and degradation of misfolded proteins - Cancer biology, where its overexpression can contribute to tumour progression and resistance to therapy - Neurodegenerative diseases, given its role in preventing protein aggregation, which is a hallmark of conditions like Alzheimer’s and Parkinson’s disease - Immune response modulation, as it can influence cytokine production and immune cell function.

Top Products

For researchers investigating HSPA1A, we recommend two primary antibodies that stand out for their performance and reliability. The first is the well-cited Anti-Hsp70 antibody [5A5] (ab2787), a monoclonal antibody that has garnered 259 citations, underscoring its trustworthiness in the field. This antibody is versatile, suitable for a range of applications including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), flow cytometry (FC), and immunoprecipitation (IP).Additionally, we offer the recombinant antibody Anti-Hsp70 antibody [3A3] (ab5439), which is also a strong choice for HSPA1A studies. This recombinant product has been validated for use in WB, IHC, and ICC, making it an excellent option for researchers seeking batch-to-batch consistency. With 79 citations, it is gaining recognition in the research community. Together, these antibodies provide robust tools for studying HSPA1A effectively. The Anti-Hsp70 antibody ELISA Kit (ab182844), supported by 2 citations, is an excellent option for researchers looking to measure HSPA1A levels with confidence.

Abcam Product Citation Summary

The data indicates a diverse range of studies involving the HSPA1A target across various species, including humans, pigs, and rats. The applications primarily focus on Western blotting, with some studies also employing immunohistochemistry. The contexts of these studies include responses to environmental stressors, disease mechanisms, and cellular responses, highlighting the importance of HSPA1A in various biological processes.

Abcam Product Citation Table

Domain

The N-terminal nucleotide binding domain (NBD) (also known as the ATPase domain) is responsible for binding and hydrolyzing ATP. The C-terminal substrate-binding domain (SBD) (also known as peptide-binding domain) binds to the client/substrate proteins. The two domains are allosterically coupled so that, when ATP is bound to the NBD, the SBD binds relatively weakly to clients. When ADP is bound in the NBD, a conformational change enhances the affinity of the SBD for client proteins.

Function

Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation. This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones. The co-chaperones have been shown to not only regulate different steps of the ATPase cycle, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation. The affinity for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. It goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The co-chaperones are of three types: J-domain co-chaperones such as HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP-bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1 (PubMed:24012426, PubMed:24318877, PubMed:26865365). Maintains protein homeostasis during cellular stress through two opposing mechanisms: protein refolding and degradation. Its acetylation/deacetylation state determines whether it functions in protein refolding or protein degradation by controlling the competitive binding of co-chaperones HOPX and STUB1. During the early stress response, the acetylated form binds to HOPX which assists in chaperone-mediated protein refolding, thereafter, it is deacetylated and binds to ubiquitin ligase STUB1 that promotes ubiquitin-mediated protein degradation (PubMed:27708256). Regulates centrosome integrity during mitosis, and is required for the maintenance of a functional mitotic centrosome that supports the assembly of a bipolar mitotic spindle (PubMed:27137183). Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling (PubMed:24613385). Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223). Required as a co-chaperone for optimal STUB1/CHIP ubiquitination of NFATC3 (By similarity). Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401). Involved in the clearance of misfolded PRDM1/Blimp-1 proteins. Sequesters them in the cytoplasm and promotes their association with SYNV1/HRD1, leading to proteasomal degradation (PubMed:28842558).

(Microbial infection) In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell.

Involvement in disease

In certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), plays a role in the cytoplasmic sequestration of misfolded N-terminal mutated PRDM1 proteins, promotes their association with SYNV1/HRD1 and degradation through the SYNV1-proteasome pathway. HSPA1A inhibition restores PRDM1 nuclear localization and transcriptional activity in lymphoma cell lines and suppresses growth in xenografts.

Post-translational modifications

In response to cellular stress, acetylated at Lys-77 by NA110 and then gradually deacetylated by HDAC4 at later stages. Acetylation enhances its chaperone activity and also determines whether it will function as a chaperone for protein refolding or degradation by controlling its binding to co-chaperones HOPX and STUB1. The acetylated form and the non-acetylated form bind to HOPX and STUB1 respectively. Acetylation also protects cells against various types of cellular stress.

Sequence Similarities

Belongs to the heat shock protein 70 family.

Cellular localization

• Cytoplasm
• Nucleus
• Cytoplasm
• Cytoskeleton
• Microtubule organizing center
• Centrosome
• Secreted
• Localized in cytoplasmic mRNP granules containing untranslated mRNAs.

Alternative names

HSP72, HSPA1, HSX70, HSPA1A, Heat shock 70 kDa protein 1A, Heat shock 70 kDa protein 1, Heat shock protein family A member 1A, HSP70-1, HSP70.1

Database links

swissprot:P0DMV8 omim:140550 omim:603012 swissprot:P0DMV9 entrezGene:3303 entrezGene:3304 entrezGene:15511

Other research areas

• Neuroscience
• Oncology