UniProt functional annotation for Q99933



	UniProt functional annotation for Q99933

UniProt code: Q99933.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:27474739, PubMed:9873016, PubMed:24318877). Inhibits the pro-apoptotic function of PPP1R15A, and has anti-apoptotic activity (PubMed:12724406). Markedly increases the anti-cell death function of BCL2 induced by various stimuli (PubMed:9305631). {ECO:0000269|PubMed:12724406, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:9305631, ECO:0000269|PubMed:9873016}.

Subunit: Homodimer. Forms a heteromeric complex with HSP70/HSC70 (PubMed:9305631). Binds to the ATPase domain of HSP/HSC70 chaperones. Isoform 1, isoform 3 and isoform 4 but not isoform 2 interact with HSPA8/HSC70 (PubMed:27474739, PubMed:24318877, PubMed:9305631, PubMed:9679980). Interacts with NR3C1 (PubMed:10477749). Interacts with the N-terminal region of STK19 (PubMed:15986447). Interacts with PPP1R15A (PubMed:12724406). Interacts with BCL2 in an ATP-dependent manner. Isoform 2 does not interact with BCL2 (PubMed:9305631). Interacts with SIAH1 (PubMed:9582267). Interacts with HSPA8 (via NBD) (PubMed:27474739, PubMed:24318877). Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). Interacts with SIAH2 (By similarity). {ECO:0000250|UniProtKB:Q60739, ECO:0000269|PubMed:10477749, ECO:0000269|PubMed:11222862, ECO:0000269|PubMed:12724406, ECO:0000269|PubMed:15986447, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:9305631, ECO:0000269|PubMed:9582267, ECO:0000269|PubMed:9679980}.

Subcellular location: [Isoform 1]: Nucleus. Cytoplasm. Note=Isoform 1 localizes predominantly to the nucleus.

Subcellular location: [Isoform 2]: Cytoplasm. Nucleus. Note=Isoform 2 localizes to the cytoplasm and shuttles into the nucleus in response to heat shock.

Subcellular location: [Isoform 4]: Cytoplasm. Nucleus. Note=Isoform 4 localizes predominantly to the cytoplasm. The cellular background in which it is expressed can influence whether it resides primarily in the cytoplasm or is also found in the nucleus. In the presence of BCL2, localizes to intracellular membranes (what appears to be the nuclear envelope and perinuclear membranes) as well as punctate cytosolic structures suggestive of mitochondria.

Tissue specificity: Isoform 4 is the most abundantly expressed isoform. It is ubiquitously expressed throughout most tissues, except the liver, colon, breast and uterine myometrium. Isoform 1 is expressed in the ovary and testis. Isoform 4 is expressed in several types of tumor cell lines, and at consistently high levels in leukemia and lymphoma cell lines. Isoform 1 is expressed in the prostate, breast and leukemia cell lines. Isoform 3 is the least abundant isoform in tumor cell lines (at protein level). {ECO:0000269|PubMed:9679980}.

Induction: Up-regulated during differentiation of bladder epithelial cells and down-regulated during differentiation of prostate epithelium. {ECO:0000269|PubMed:9679980}.

Ptm: Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation. {ECO:0000305}.

Miscellaneous: [Isoform 2]: Produced by alternative splicing. {ECO:0000305}.

Miscellaneous: [Isoform 3]: Produced by alternative initiation at Met- 72 of isoform 1. {ECO:0000305}.

Miscellaneous: [Isoform 4]: Produced by alternative initiation at Met- 116 of isoform 1. {ECO:0000305}.

Sequence caution: Sequence=AAD11467.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAD25045.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAD96469.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305}; Sequence=CAA84624.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=EAW58515.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70 (PubMed:27474739, PubMed:9873016, PubMed:24318877). Inhibits the pro-apoptotic function of PPP1R15A, and has anti-apoptotic activity (PubMed:12724406). Markedly increases the anti-cell death function of BCL2 induced by various stimuli (PubMed:9305631). {ECO:0000269\|PubMed:12724406, ECO:0000269\|PubMed:24318877, ECO:0000269\|PubMed:27474739, ECO:0000269\|PubMed:9305631, ECO:0000269\|PubMed:9873016}.


Subunit:		Homodimer. Forms a heteromeric complex with HSP70/HSC70 (PubMed:9305631). Binds to the ATPase domain of HSP/HSC70 chaperones. Isoform 1, isoform 3 and isoform 4 but not isoform 2 interact with HSPA8/HSC70 (PubMed:27474739, PubMed:24318877, PubMed:9305631, PubMed:9679980). Interacts with NR3C1 (PubMed:10477749). Interacts with the N-terminal region of STK19 (PubMed:15986447). Interacts with PPP1R15A (PubMed:12724406). Interacts with BCL2 in an ATP-dependent manner. Isoform 2 does not interact with BCL2 (PubMed:9305631). Interacts with SIAH1 (PubMed:9582267). Interacts with HSPA8 (via NBD) (PubMed:27474739, PubMed:24318877). Interacts with HSPA1A (via NBD) and HSPA1B (via NBD) (PubMed:24318877). Interacts with SIAH2 (By similarity). {ECO:0000250\|UniProtKB:Q60739, ECO:0000269\|PubMed:10477749, ECO:0000269\|PubMed:11222862, ECO:0000269\|PubMed:12724406, ECO:0000269\|PubMed:15986447, ECO:0000269\|PubMed:24318877, ECO:0000269\|PubMed:27474739, ECO:0000269\|PubMed:9305631, ECO:0000269\|PubMed:9582267, ECO:0000269\|PubMed:9679980}.
Subcellular location:		[Isoform 1]: Nucleus. Cytoplasm. Note=Isoform 1 localizes predominantly to the nucleus.
Subcellular location:		[Isoform 2]: Cytoplasm. Nucleus. Note=Isoform 2 localizes to the cytoplasm and shuttles into the nucleus in response to heat shock.
Subcellular location:		[Isoform 4]: Cytoplasm. Nucleus. Note=Isoform 4 localizes predominantly to the cytoplasm. The cellular background in which it is expressed can influence whether it resides primarily in the cytoplasm or is also found in the nucleus. In the presence of BCL2, localizes to intracellular membranes (what appears to be the nuclear envelope and perinuclear membranes) as well as punctate cytosolic structures suggestive of mitochondria.
Tissue specificity:		Isoform 4 is the most abundantly expressed isoform. It is ubiquitously expressed throughout most tissues, except the liver, colon, breast and uterine myometrium. Isoform 1 is expressed in the ovary and testis. Isoform 4 is expressed in several types of tumor cell lines, and at consistently high levels in leukemia and lymphoma cell lines. Isoform 1 is expressed in the prostate, breast and leukemia cell lines. Isoform 3 is the least abundant isoform in tumor cell lines (at protein level). {ECO:0000269\|PubMed:9679980}.
Induction:		Up-regulated during differentiation of bladder epithelial cells and down-regulated during differentiation of prostate epithelium. {ECO:0000269\|PubMed:9679980}.
Ptm:		Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation. {ECO:0000305}.
Miscellaneous:		[Isoform 2]: Produced by alternative splicing. {ECO:0000305}.
Miscellaneous:		[Isoform 3]: Produced by alternative initiation at Met- 72 of isoform 1. {ECO:0000305}.
Miscellaneous:		[Isoform 4]: Produced by alternative initiation at Met- 116 of isoform 1. {ECO:0000305}.
Sequence caution:		Sequence=AAD11467.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=AAD25045.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=BAD96469.1; Type=Miscellaneous discrepancy; Note=Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.; Evidence={ECO:0000305}; Sequence=CAA84624.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; Sequence=EAW58515.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};