HSPA8

GeneName

HSPA8

Summary

HSPA8, also known as Hsc70, is a 71 kDa heat shock protein that functions primarily as a molecular chaperone. It is expressed in various tissues and localises to multiple cellular compartments, including the cytoplasm, nucleus, lysosomes, and plasma membrane. HSPA8 plays a critical role in protein folding, refolding, and transport, facilitating the proper assembly and disassembly of protein complexes. It is involved in processes such as chaperone-mediated autophagy and the cellular response to stress, particularly in response to unfolded proteins. Additionally, HSPA8 binds to ATP and has various interactions with other proteins, including MHC class II complexes and G protein-coupled receptors, highlighting its diverse functional roles in cellular homeostasis and signalling.

Importance

HSPA8 is relevant to: - Protein misfolding diseases, as it assists in the refolding and degradation of misfolded proteins. - Cancer biology, given its role in regulating cell migration and survival under stress conditions. - Neurodegenerative disorders, where it may influence the aggregation of proteins associated with diseases such as Alzheimer’s. - Immune responses, due to its involvement in MHC class II antigen presentation and modulation of inflammation through its regulatory functions.

Top Products

For researchers investigating HSPA8, we highly recommend the top-selling recombinant antibody, Anti-Hsc70 antibody [EP1531Y] (ab51052). This well-cited antibody has garnered 74 citations, reflecting its reliability and trust within the scientific community. It has been validated in knockout models and is suitable for a variety of applications, including Western blotting (WB), immunocytochemistry (ICC), immunohistochemistry (IHC), immunoprecipitation (IP), and flow cytometry (FC). This versatility makes it an excellent choice for those seeking consistent and effective detection of HSPA8 in their experiments.

Abcam Product Citation Summary

The data indicates that the HSPA8 target is primarily studied in human cell lines, particularly HeLa and PC12 cells, focusing on lysosomal activity, degradation processes, and the role of extracellular vesicles. The use of Western blotting and immunofluorescence suggests a strong interest in the protein's expression and localisation in various cellular contexts.

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, chaperone-mediated autophagy, activation of proteolysis of misfolded proteins, formation and dissociation of protein complexes, and antigen presentation. 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 (PubMed:21148293, PubMed:21150129, PubMed:23018488, PubMed:24732912, PubMed:27916661, PubMed:2799391, PubMed:36586411). This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:12526792, PubMed:21148293, PubMed:21150129, PubMed:23018488, PubMed:24732912, PubMed:27916661). The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation (PubMed:12526792, PubMed:21148293, PubMed:21150129, PubMed:23018488, PubMed:24732912, PubMed:27916661). The affinity of HSP70 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. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J-domain co-chaperones 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:24121476, PubMed:24318877, PubMed:26865365, PubMed:27474739). Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 (PubMed:12526792). Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:10722728, PubMed:11276205). Substrate recognition component in chaperone-mediated autophagy (CMA), a selective protein degradation process that mediates degradation of proteins with a -KFERQ motif: HSPA8/HSC70 specifically recognizes and binds cytosolic proteins bearing a -KFERQ motif and promotes their recruitment to the surface of the lysosome where they bind to lysosomal protein LAMP2 (PubMed:11559757, PubMed:2799391, PubMed:36586411). KFERQ motif-containing proteins are eventually transported into the lysosomal lumen where they are degraded (PubMed:11559757, PubMed:2799391, PubMed:36586411). In conjunction with LAMP2, facilitates MHC class II presentation of cytoplasmic antigens by guiding antigens to the lysosomal membrane for interaction with LAMP2 which then elicits MHC class II presentation of peptides to the cell membrane (PubMed:15894275). Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1 (PubMed:23990462). It is recruited to clathrin-coated vesicles through its interaction with DNAJC6 leading to activation of HSPA8/HSC70 ATPase activity and therefore uncoating of clathrin-coated vesicles (By similarity).

Post-translational modifications

Acetylated.

ISGylated.

Trimethylation at Lys-561 reduces fibrillar SNCA binding.

Sequence Similarities

Belongs to the heat shock protein 70 family.

Tissue Specificity

Ubiquitous.

Cellular localization

• Cytoplasm
• Melanosome
• Nucleus
• Nucleolus
• Cell membrane
• Lysosome membrane
• Peripheral membrane protein
• Cytoplasmic side
• Localized in cytoplasmic mRNP granules containing untranslated mRNAs (PubMed:17289661). Translocates rapidly from the cytoplasm to the nuclei, and especially to the nucleoli, upon heat shock (PubMed:1586970).

Alternative names

HSC70, HSP73, HSPA10, HSPA8, Heat shock cognate 71 kDa protein, Heat shock 70 kDa protein 8, Heat shock protein family A member 8, Lipopolysaccharide-associated protein 1, LAP-1, LPS-associated protein 1

Database links

swissprot:P11142 swissprot:P0DMV9 entrezGene:3303 entrezGene:15511 entrezGene:3312 omim:140550 omim:603012 omim:600816 swissprot:P0DMV8