DegronMD - P11021(HSPA5)

FUNCTION: Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166). {ECO:0000250|UniProtKB:G3I8R9, ECO:0000250|UniProtKB:P20029, ECO:0000269|PubMed:1550958, ECO:0000269|PubMed:19538957, ECO:0000269|PubMed:2294010, ECO:0000269|PubMed:23769672, ECO:0000269|PubMed:23990668, ECO:0000269|PubMed:26045166, ECO:0000269|PubMed:28332555, ECO:0000269|PubMed:29719251}.; FUNCTION: (Microbial infection) Plays an important role in viral binding to the host cell membrane and entry for several flaviruses such as Dengue virus, Zika virus and Japanese encephalitis virus (PubMed:33432092, PubMed:15098107, PubMed:28053106). Acts as a component of the cellular receptor for Dengue virus serotype 2/DENV-2 on human liver cells (PubMed:15098107). {ECO:0000269|PubMed:15098107, ECO:0000269|PubMed:28053106, ECO:0000269|PubMed:33432092}.; FUNCTION: (Microbial infection) Acts as a receptor for CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:24355926, PubMed:20484814, PubMed:32487760). Acts as a receptor for R.delemar CotH3 in nasal epithelial cells, which may be an early step in rhinoorbital/cerebral mucormycosis (RCM) disease progression (PubMed:32487760). {ECO:0000269|PubMed:20484814, ECO:0000269|PubMed:24355926, ECO:0000269|PubMed:32487760}. View more >>

GO - Biological processes (BP): cellular response to antibiotic [GO:0071236]; cellular response to calcium ion [GO:0071277]; cellular response to cAMP [GO:0071320]; cellular response to gamma radiation [GO:0071480]; cellular response to glucose starvation [GO:0042149]; cellular response to interleukin-4 [GO:0071353]; cellular response to manganese ion [GO:0071287]; cellular response to nerve growth factor stimulus [GO:1990090]; cellular response to unfolded protein [GO:0034620]; cellular response to xenobiotic stimulus [GO:0071466]; cerebellar Purkinje cell layer development [GO:0021680]; cerebellum structural organization [GO:0021589]; chaperone cofactor-dependent protein refolding [GO:0051085]; endoplasmic reticulum unfolded protein response [GO:0030968]; ER overload response [GO:0006983]; luteolysis [GO:0001554]; maintenance of protein localization in endoplasmic reticulum [GO:0035437]; negative regulation of apoptotic process [GO:0043066]; negative regulation of IRE1-mediated unfolded protein response [GO:1903895]; negative regulation of protein-containing complex assembly [GO:0031333]; negative regulation of transforming growth factor beta receptor signaling pathway [GO:0030512]; neuron apoptotic process [GO:0051402]; neuron differentiation [GO:0030182]; positive regulation of cell migration [GO:0030335]; positive regulation of neuron projection development [GO:0010976]; positive regulation of protein ubiquitination [GO:0031398]; positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress [GO:1990440]; posttranslational protein targeting to membrane, translocation [GO:0031204]; protein folding in endoplasmic reticulum [GO:0034975]; protein refolding [GO:0042026]; regulation of ATF6-mediated unfolded protein response [GO:1903891]; regulation of IRE1-mediated unfolded protein response [GO:1903894]; regulation of PERK-mediated unfolded protein response [GO:1903897]; regulation of protein folding in endoplasmic reticulum [GO:0060904]; response to cocaine [GO:0042220]; response to methamphetamine hydrochloride [GO:1904313]; stress response to metal ion [GO:0097501]; substantia nigra development [GO:0021762]; toxin transport [GO:1901998]; ubiquitin-dependent ERAD pathway [GO:0030433] 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.E71K	TCGA-AC-A2B8	BRCA	TCGA	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.591
p.E71K	DO5884	BRCA	ICGC	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.591
p.P70T	TCGA-DD-A4NP	LIHC	TCGA	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.7031
p.P70T	DO44958	LIHC	ICGC	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.7031
p.G72V	TCGA-EE-A2GH	SKCM	TCGA	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.6421
p.G72V	DO37643	SKCM	ICGC	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.6421
p.T69P	ACH-000354	Pancreatic Cancer	CCLE	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.8142
p.T69P	CAPAN-1	pancreas	COSMIC	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.8142
p.A67T	KARPAS-45	haematopoietic and lymphoid tissue	COSMIC	VAFTPEGE	DEG_SCF_FBW7_2	66:73	Mutation altering degron motif	0.6028

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

HSPA5

UniProt ID: P11021

Entrez ID: 3309

Protein name: Endoplasmic reticulum chaperone BiP (EC 3.6.4.10) (78 kDa glucose-regulated protein) (GRP-78) (Binding-immunoglobulin protein) (BiP) (Heat shock protein 70 family protein 5) (HSP70 family protein 5) (Heat shock protein family A member 5) (Immunoglobulin heavy chain-binding protein)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for HSPA5 in