Search results for FKBP4

Showing 13 results out of 14

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Species

Types

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Protein (3 results from a total of 3)

Identifier: R-HSA-8939162
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: FKBP4: Q02790
Identifier: R-HSA-5324621
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: FKBP4: Q02790
Identifier: R-HSA-5618108
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q02790

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-4793843
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSG00000004478

Reaction (5 results from a total of 6)

Identifier: R-HSA-5618085
Species: Homo sapiens
Compartment: cytosol
FKBP52 (also known as the large immunophilin FKBP4) is a co-chaperone containing tetratricopeptide repeat (TPR) domain, which binds the C-terminal sequence motif (MEEVD) of HSP90 (Wu B et al. 2004; Davies and Sanchez 2005). The stoichiometry of FKBP in receptor heterocomplexes was determined on the basis of the size of cross-linked complexes, a ratio of one molecule of receptor and two molecules of HSP90 to one molecule of FKBP52 was obtained for human PR , ER and mouse GR (Rexin M et al. 1992; Rehberger P et al. 1992; Segnitz B and Gehring U 1995). Mass spectrometry analysis showed that FKBP51 (FKBP5) and FKBP52 (FKBP4) form analogous complexes with GR:HSP90:STIP1:HSP70:ATP (Ebong IO et al. 2016). Binding of FKBP52 (FKBP4) and other immunophilins may weaken the association of TPR domain containing protein STIP1 with HSP90 complex (Li et al. 2011).

FKBP52 (FKBP4) is a member of the immunophilin (IMM) protein family of intracellular proteins that are able to bind immunosuppressant drugs, from which the term immunophilin derives (Pratt and Toft 1997; Kang et al. 2008). These proteins are also known as peptidyl-prolyl cis/trans isomerases (PPIases) for their ability to convert proline bonds from cis to trans form, a rate-limiting step in protein folding (Harding et al. 1989; Standaert et al. 1990; Galat 2003; Davies and Sanchez 2005). In addition to the PPIase and TPR domains, there are two additional domains - the nucleotide-binding domain (also called FKBD2 in FKBP proteins) where ATP binds and the calmodulin-binding domain, a poorly characterized domain able to interact with calmodulin.

Identifier: R-HSA-5618073
Species: Homo sapiens
Compartment: cytosol
Mass spectrometry analysis showed that FKBP51 (FKBP5) and FKBP52 (FKBP4) form analogous complexes with GR:HSP90:STIP1:HSP70:ATP (Ebong IO et al. 2016). Without hormone, FKBP51 is the major immunophilin in GR:HSP90 complexes, whereas after hormone treatment, FKBP52 rapidly replaces FKBP51 (Davies et al., 2002).
Identifier: R-HSA-5324617
Species: Homo sapiens
Compartment: nucleoplasm
Under non-stress conditions monomeric HSF1 is sequestered in a HSP90-containing heterocomplex. FKBP4 (immunophilin) is one of the components of HSP90-chaperone machinery which was found to associate with trimeric, but not monomeric form of HSF1 (Guo Y et al. 2001). Multichaperone complex of HSP90:FKBP4:PKGES3 has been shown to associate with HSF1 trimer through its regulatory domain, and this is thought to repress HSF1 transcriptional activity (Guo Y et al. 2001).

Identifier: R-HSA-5618110
Species: Homo sapiens
Compartment: cytosol
Immunophilin p23 (also known as PTGES3) binds selectively to the ATP-bound state of HSP90. p23 stabilizes the closed state of HSP90, which weakens the binding of STIP1(HOP) and promotes its exit from the complex (McLaughlin H et al. 2006; Karagöz GE et al. 2011). When p23 is added to the client-transfer complex in the absence of the immunophilin or with FKBP51 (FKBP5), two copies of p23 are incorporated with concomitant loss of HSP70 and HOP (Ebong I et al. 2016). By contrast no stable complex with two p23 subunits is observed in the presence of FKBP52 (FKBP4); expulsion of HSP70, HOP and p23 occur with a low population of a complex incorporating only one p23 subunit (Ebong I et al. 2016).
Identifier: R-HSA-5618105
Species: Homo sapiens
Compartment: cytosol
FK506 binding protein 5 (FKBP51, also known as FKBP5) is a member of the immunophilin (IMM) protein family of intracellular proteins. The signature domain of the IMM family is the peptidyl-prolyl-cis/trans-isomerase (PPIase) domain, which is in turn the drug binding domain. IMMs are classified by their ability to bind immunosuppressant drugs – CyPs (cyclophilins) bind cyclosporine A (CsA), and FKBPs (FK506-binding pro-teins) bind FK506 (Pratt and Toft 1997; Kang et al. 2008). In addition to the PPIase domain, there are three additional domains – the nucleotide-binding domain, (also called FKBD2 in FKBP proteins) where ATP binds, the calmodulin-binding domain, a poorly characterized domain able to interact with calmodulin, and tetratricopeptide repeat (TPR) domains, sequences of 34 amino acids repeated in tandem through which FKBPs bind to the HSP90 C-terminal sequence MEEVD (Davies et al. 2005; Wu et al. 2004). Mass spectrometry analysis showed that FKBP51 (FKBP5) and FKBP52 (FKBP4) form analogous complexes with GR:HSP90:STIP1:HSP70:ATP (Ebong IO et al. 2016). Binding of FKBP51 (FKBP5) and other immunophilins may weaken the association of TPR domain containing protein STIP1 with HSP90 complex (Li et al. 2011).

Complex (2 results from a total of 2)

Identifier: R-HSA-5324622
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5324619
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (1 results from a total of 1)

Identifier: R-HSA-3371497
Species: Homo sapiens
Compartment: cytosol
Steroid hormone receptors (SHR) are transcription factors that become activated upon sensing steroid hormones such as glucocorticoids, mineralocorticoids, progesterone, androgens, or estrogen (Escriva et al 2000; Griekspoor A et al. 2007; Eick GN & Thornton JW. 2011). Depending on SHR type and the presence of ligand, they show different subcellular localizations. Whereas both unliganded and liganded estrogen receptors (ERalpha and ERbeta) are predominantly nuclear, unliganded glucocorticoid (GR) and androgen receptors (AR) are mostly located in the cytoplasm and completely translocate to the nucleus only after binding hormone (Htun H et al. 1999; Stenoien D et al. 2000; Tyagi RK et al. 2000; Cadepond F et al. 1992; Jewell CM et al. 1995; Kumar S et al. 2006). The unliganded mineralocorticoid receptor (MR) is partially cytoplasmic but can be found in nucleus in the ligand-bound or ligand-free form (Nishi M & Kawata M 2007). The progesterone receptor (PR) exists in two forms (PRA and PRB) with different ratios of nuclear versus cytoplasmic localization of the unliganded receptor. In most cell contexts, the PRA isoform is a repressor of the shorter PRB isoform, and without hormone induction it is mostly located in the nucleus, whereas PRB distributes both in the nucleus and in the cytoplasm (Lim CS et al. 1999; Griekspoor A et al. 2007). In the absence of ligand, members of the steroid receptor family remain sequestered in the cytoplasm and/or nucleus in the complex with proteins of HSP70/HSP90 chaperone machinery (Pratt WB & Dittmar KD1998). The highly dynamic ATP-dependent interactions of SHRs with HSP90 complexes regulate SHR cellular location, protein stability, competency to bind steroid hormones and transcriptional activity (Echeverria PC & Picard D 2010). Understanding the mechanism of ATPase activity of HSP90 is mostly based on structural and functional studies of the Saccharomyces cerevisiae Hsp90 complexes (Meyer P et al. 2003, 2004; Ali MM et al. 2006; Prodromou C et al. 2000; Prodromou C 2012). The ATPase cycle of human HSP90 is less well understood, however several studies suggest that the underlying enzymatic mechanisms and a set of conformational changes that accompany the ATPase cycle are highly similar in both species (Richter K et al. 2008; Vaughan CK et al. 2009). Nascent SHR proteins are chaperoned by HSP70 and HSP40 to HSP90 cycle via STIP1 (HOP) (and its TPR domains) (Hernández MP et al. 2002a,b; EcheverriaPC & Picard D 2010; Li J et al. 2011). The ATP-bound form of HSP90 leads to the displacement of STIP1 by immunophilins FKBP5 or FKBP4 resulting in conformational changes that allow efficient hormone binding (Li J et al. 2011). PTGES3 (p23) binds to HSP90 complex finally stabilizing it in the conformation with a high hormone binding affinity. After hydrolysis of ATP the hormone bound SHR is released from HSP90 complex. The cytosolic hormone-bound SHR can be transported to the nucleus by several import pathways such as the dynein-based nuclear transport along microtubules involving the transport of the entire HSP90 complex or nuclear localization signals (NLS)-mediated nuclear targeting by importins (Tyagi RK et al. 2000; Cadepond F et al. 1992; Jewell CM et al. 1995; Kumar S et al. 2006). It is worth noting that GR-importin interactions can be ligand-dependent or independent (Freedman & Yamamoto 2004; Picard & Yamamoto 1987). In the nucleus ligand-activated SHR dimerizes, binds specific sequences in the DNA, called Hormone Responsive Elements (HRE), and recruits a number of coregulators that facilitate gene transcription. Nuclear localization is essential for SHRs to transactivate their target genes, but the same receptors also possess non-genomic functions in the cytoplasm.

The Reactome module describes the ATPase-driven conformational cycle of HSP90 that regulates ligand-dependent activation of SHRs.

Icon (1 results from a total of 1)

Species: Homo sapiens
Peptidyl-prolyl cis-trans isomerase FKBP4
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