DegronMD - P11142(HSPA8)

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 (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488). This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). 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:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488, PubMed:12526792). 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:24318877, PubMed:27474739, PubMed:24121476, PubMed:26865365). 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). 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). Interacts with VGF-derived peptide TLQP-21 (PubMed:28934328). {ECO:0000269|PubMed:10722728, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:12526792, ECO:0000269|PubMed:21148293, ECO:0000269|PubMed:21150129, ECO:0000269|PubMed:23018488, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:24732912, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:27916661, ECO:0000269|PubMed:28934328, ECO:0000303|PubMed:24121476, ECO:0000303|PubMed:26865365}. View more >>

GO - Biological processes (BP): View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.L486P	TCGA-BP-5195	KIRC	TCGA	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0556
p.L486P	DO18026	KIRC	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0556
p.N487S	TCGA-DK-AA74	BLCA	TCGA	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0833
p.N487S	TCGA-ZG-A9N3	PRAD	TCGA	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0833
p.N487S	DO219011	BLCA	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0833
p.N487S	DO219446	PRAD	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0833
p.E498D	TCGA-IN-A6RP	STAD	TCGA	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation altering degron motif	0.6758
p.E498D	DO51741	STAD	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation altering degron motif	0.6758
p.V491L	TCGA-OR-A5KB	ACC	TCGA	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1944
p.T504N	DO229019	LICA	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.2222
p.T495K	DO217836	ORCA	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.3056
p.L510V	DO231344	THCA	ICGC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.0556
p.I501T	SIDM00220	Ovarian Carcinoma	GDSC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.3056
p.I501T	ACH-000962	Ovarian Cancer	CCLE	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.3056
p.I501T	ACH-001145	Ovarian Cancer	CCLE	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.3056
p.I501T	OC-314	ovary	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.3056
p.N505D	SIDM01608	Endometrial Carcinoma	GDSC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1944
p.N505D	ACH-000990	Endometrial/Uterine Cancer	CCLE	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1944
p.E497K	SW900	lung	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation altering degron motif	0.7022
p.E491Q	HDQ-P1	breast	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1944
p.E490K	SW900	lung	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1667
p.E490V	NCI-H1648	lung	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation rewiring degron network	0.1667
p.E498Q	HDQ-P1	breast	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation altering degron motif	0.6744
p.E497V	NCI-H1648	lung	COSMIC	GKENK	DEG_APCC_KENBOX_2	496:500	Mutation altering degron motif	0.7693

DegronMD: protein-targeted degradation, mutation and drug response to degrons

HSPA8

UniProt ID: P11142

Entrez ID: 3312

Protein name: Heat shock cognate 71 kDa protein (EC 3.6.4.10) (Heat shock 70 kDa protein 8) (Lipopolysaccharide-associated protein 1) (LAP-1) (LPS-associated protein 1)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for HSPA8 in