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 pr (updated: Oct. 10, 2018)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology.

Total structural coverage: 95%

Model score: 87

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Variant	Description
	dbSNP:rs562047

No binding partner found

Biological Process

ATP metabolic process

Cellular heat acclimation

Cellular response to heat

Cellular response to oxidative stress

Cellular response to unfolded protein

Chaperone cofactor-dependent protein refolding

Chaperone-mediated protein complex assembly

Lysosomal transport

MRNA catabolic process

Negative regulation of apoptotic process

Negative regulation of cell death

Negative regulation of cell growth

Negative regulation of cell population proliferation

Negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

Negative regulation of extrinsic apoptotic signaling pathway in absence of ligand

Negative regulation of inclusion body assembly

Negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway

Negative regulation of protein ubiquitination

Negative regulation of transcription from RNA polymerase II promoter in response to stress

Negative regulation of transforming growth factor beta receptor signaling pathway

Neutrophil degranulation

Positive regulation of endoribonuclease activity

Positive regulation of erythrocyte differentiation

Positive regulation of gene expression

Positive regulation of interleukin-8 production

Positive regulation of microtubule nucleation

Positive regulation of NF-kappaB transcription factor activity

Positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway

Positive regulation of proteasomal ubiquitin-dependent protein catabolic process

Positive regulation of RNA splicing

Positive regulation of tumor necrosis factor-mediated signaling pathway

Protein refolding

Protein stabilization

Regulation of cellular response to heat

Regulation of mitotic spindle assembly

Regulation of mRNA stability

Regulation of protein ubiquitination

Response to unfolded protein

Vesicle-mediated transport

Cellular Component

Aggresome

Blood microparticle

Centriole

Centrosome

Cytoplasm

Cytosol

Endoplasmic reticulum

Extracellular exosome

Extracellular region

Ficolin-1-rich granule lumen

Focal adhesion

Inclusion body

Mitochondrion

Nuclear speck

Nucleoplasm

Nucleus

Perinuclear region of cytoplasm

Plasma membrane

Protein-containing complex

Ribonucleoprotein complex

Vesicle

Molecular Function

ATP binding

ATPase

ATPase activity, coupled

C3HC4-type RING finger domain binding

Cadherin binding

Denatured protein binding

Disordered domain specific binding

Enzyme binding

G protein-coupled receptor binding

Heat shock protein binding

Histone deacetylase binding

Misfolded protein binding

Protein folding chaperone

Protein N-terminus binding

RNA binding

Signaling receptor binding

Transcription corepressor activity

Ubiquitin protein ligase binding

Unfolded protein binding

Virus receptor activity

The reference OMIM entry for this protein is 140550

Heat-shock 70-kd protein 1a; hspa1a
Heat-shock 70-kd protein 1; hspa1
Heat-shock protein, 70-kd, 1
Hsp70-1
Hsp70-1a
Hsp72
Heat-shock 70-kd protein, inducible; hsp70i

CLONING

A number of organisms, such as Drosophila, respond to elevated temperature by synthesizing a small number of specific proteins. This phenomenon occurs also in yeast and in cultured HeLa cells. Exposure of HeLa cells to a temperature of 45 degrees C for 10 minutes leads to an increased synthesis of at least 3 sets of proteins with molecular masses of about 100,000, 72,000-74,000, and 37,000 daltons (Slater et al., 1981). The phenomenon is blocked by actinomycin D, suggesting transcriptional control. In vitro translation of cytoplasmic RNA from heat-shocked cells, followed by 2-D gel analysis of the translation products, shows that the major 72,000- to 74,000-dalton band consists of 7 polypeptides, designated alpha, alpha-prime, beta, gamma, delta, epsilon, and zeta. The increase in synthesis of the heat-shock proteins begins soon after heat treatment but does not reach a maximum until 2 hours later. The pattern of induction suggests coordinate regulation. To study this, Cato et al. (1981) cloned the cDNA sequences encoding the beta, gamma, delta, and epsilon heat-shock polypeptides. Hickey et al. (1986) isolated cDNA clones representing at least 5 distinct heat-inducible mRNAs in human cells. Milner and Campbell (1990) determined that the HSPA1A gene encodes a predicted 641-amino acid protein. By Northern blot analysis of HeLa cell RNA, they detected an approximately 2.4-kb HSPA1A transcript that was constitutively expressed at low levels and was induced following heat shock.

GENE FUNCTION

While the function of the ubiquitous, highly conserved heat-shock proteins was unknown, an intriguing relationship between expression of heat-shock proteins and transformation had been observed. Pelham (1986) speculated on the function of heat-shock proteins. Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1 (601324), which complexes with heat-shock proteins HSC70 (600816) and HSP70, translation initiation factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Laroia et al. (1999) found that induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway. During adenovirus late infection, or heat shock of cells, translation of most capped cellular mRNAs is inhibited and adenovirus late mRNAs are translated by a mechanism called ribosome shunting. In shunting, ribosomes are loaded onto mRNA by a cap-dependent process, but then shunt or bypass large segments of the mRNA before initiating translation at a downstream AUG. Ribosome shunting is mediated by the 5-prime noncoding region of adenovirus mRNAs, called the tripartite leader, which shares striking complementarity to 18S rRNAs. Yueh and Schneider (2000) found that the 5-prime noncoding region of human HSP70 mRNA contains an element related to the adenovirus tripartite leader sequence. This element promoted ribosome shunting for HSP70 expression during heat shock when cap-dependent protein synthesis was blocked. Unfold ... More on the omim web site

Subscribe to this protein entry history

Feb. 23, 2019: Protein entry updated
Automatic update: comparative model was added.

Feb. 23, 2019: Protein entry updated
Automatic update: model status changed

Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 140550 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).

Heat shock 70 kDa protein 1A (HSPA1A)