Search results for STIP1

Showing 12 results out of 17

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Protein (1 results from a total of 1)

Identifier: R-HSA-443857
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: STIP1: P31948

Complex (3 results from a total of 3)

Identifier: R-HSA-3371444
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5618095
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5618076
Species: Homo sapiens
Compartment: cytosol

Interactor (1 results from a total of 1)

Identifier: Q9UNE7-1
Species: Homo sapiens
Primary external reference: UniProt: Q9UNE7-1

Reaction (6 results from a total of 11)

Identifier: R-HSA-3371503
Species: Homo sapiens
Compartment: cytosol
Stress-induced phosphoprotein 1 (STIP1, also known as HSP70-HSP90-organizing protein or HOP) functions as a mediator of interaction between heat shock protein (HSP)70 and HSP90 as part of the cellular assembly machine. It also modulates the ATPase activity of both HSP70 and HSP90, thus facilitating client protein transfer between the two. STIP1 is a monomeric protein composed of three tetratricopeptide repeat domains (TPR1, TPR2A, TPR2B) involved in protein-protein interactions, and two small aspartic acid–proline repeat domains (DP1, DP2) involved in client activation (Scheufler C et al. 2000; Nelson GM et al. 2003; Yi F et al. 2010; Schmid AB et al. 2012). A flexible linker of STIP1 (HOP) connects TPR1-DP1 and TPR2A-TPR2B-DP2 modules arranging it as TPR1-DP1-TPR2A-TPR2B-DP2 (Scheufler C et al. 2000). Biochemical and crystallographic analysis revealed that TPR domains of STIP1 interact specifically with C-terminal MEEVD motifs of HSP70 or HSP90 chaperones; TPR2A binds preferentially to HSP90, whereas TPR1 and TPR2B bind to HSP70 (Scheufler C et al. 2000; Carrigan PE et al. 2006; Schmid AB et al. 2012). Furthermore, cryoelectron microscopy (cryo-EM) reconstruction of the human HSP90:STIP1 complex revealed that STIP1 may also form interactions in several other parts of HSP90, pre-organizing N-terminal domains (NTDs) of HSP90 and thus increasing accessibility of the nucleotide-binding pocket (Southworth DR & Agard DA 2011). STIP1 stabilizes an alternate HSP90 open state where hydrophobic client-binding surfaces of HSP90 monomers have converged remaining accessible for client loading (Southworth DR & Agard DA 2011). STIP1 is positioned with a TPR1 domain extending from the HSP90 dimer cleft remaining available for an interaction with HSP70. In the STIP1-stabilized HSP90 conformation the N-terminal domains have rotated to match the closed ATP conformation. However, the arrangement of the STIP1 domains in the complex seems to prevent the NTDs dimerization of HSP90 monomers and total closure of the HSP90 dimer that is required for an efficient HSP90-mediated ATP hydrolysis (Southworth DR & Agard DA 2011; Alvira S et al. 2014). HSP70, in the ADP state, readily binds HSP90:STIP1, forming a client-loading complex HSP90:STIP1:HSP70:client protein (Hernández MP et al. 2002). Structural studies of GR-LBD (the ligand-binding domain of the glucocorticoid receptor) bound to HSP90:STIP1:HSP70 complex showed that one STIP1 molecule binds to the HSP90 dimer and through domain rearrangement, gives rise to two main conformations, an extended structure that recognizes and interacts with HSP70, and a compact one in which HSP70 is in contact with one HSP90 monomer (Alvira S et al. 2014). Movement between these two modes is thought to deliver the HSP70-bound substrate to the side of the HSP90 dimer opposite the site of STIP1 binding (Alvira S et al. 2014). Following client delivery by HSP70 and STIP1 release, HSP90:ATP converts to the closed ATP hydrolysis-active state to complete the chaperone cycling.
Identifier: R-HSA-5618098
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 FKBP51 (FKBP5) is present, a stable intermediate FKBP51:GR:HSP90:p23 is formed by expulsion of HSP70 and STIP1(HOP) (Ebong I et al. 2016).
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-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).
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-9688838
Species: Homo sapiens
Compartment: cytosol
Receptor-interacting serine/threonine protein kinase 3 (RIPK3) functions as a key regulator of necroptosis.The protein stability of RIPK3 is negatively regulated by the C-terminus of HSC70-interacting protein (CHIP, also known as STIP1 homology and U-Box containing protein 1, STUB1) (Seo J et al. 2016). STUB1, as an E3 ligase, mediates ubiquitylation of RIPK3 at Lys55 and Lys363 and targerts it to lysosomal degradation. Coimmunoprecipitation analysis using overexpressed, endogenous or recombinant proteins revealed interactions between STUB1 (CHIP) and RIPK3 in human embryonic kidney 293T (HEK293T) cells (Seo J et al. 2016). Domain mapping revealed that the kinase domain of RIPK3 interacts with the tetratricopeptide repeat (TPR) region of STUB1 (Seo J et al. 2016). Treatment with geldanamycin (an inhibitor of HSP90) induced the degradation of RIPK3 in mouse fibroblasts L929 cells even under STUB1-depleted conditions, suggesting that HSP90 might not be involved in the STUB1-mediated degradation of RIPK3 (Seo J et al. 2016).

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.

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