Alternative titles; symbols
HGNC Approved Gene Symbol: STIP1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,185,272-64,204,543 (from NCBI)
STIP1 is an adaptor protein that coordinates the functions of HSP70 (see HSPA1A; 140550) and HSP90 (see HSP90AA1; 140571) in protein folding. It is thought to assist in the transfer of proteins from HSP70 to HSP90 by binding both HSP90 and substrate-bound HSP70. STIP1 also stimulates the ATPase activity of HSP70 and inhibits the ATPase activity of HSP90, suggesting that it regulates both the conformations and ATPase cycles of these chaperones (Song and Masison, 2005).
By microsequencing a protein that was upregulated in transformed embryonic lung fibroblasts and using degenerate PCR primers to screen a transformed embryonic lung fibroblast cDNA library, Honore et al. (1992) obtained a cDNA encoding STIP1. The predicted 543-amino acid hydrophilic protein contains a tetratricopeptide repeat (TPR), a 34-amino acid motif that is repeated at least 6 times in STIP1. STIP1 is homologous to the yeast stress-inducible mediator of the heat shock response, Sti1. Western blot analysis and 2-dimensional gel electrophoresis showed that STIP1 was expressed as an approximately 61-kD protein. Northern blot analysis showed that STIP1, which was expressed as an approximately 2.1-kb transcript, was upregulated in transformed cell lines and psoriatic keratinocytes. Immunofluorescence analysis showed that STIP1 localized to the Golgi in normal fibroblasts, but mainly to the nucleus in transformed cells.
Using mutation analysis, Chen and Smith (1998) localized a putative HSP90-binding domain to a central tetratricopeptide repeat (TPR) of the HOP sequence, and a putative HSP70-binding domain to an N-terminal TPR. Using in vitro steroid receptor assembly reactions, they found that reactions performed with HOP carrying mutations in the putative HSP70- and HSP90-binding domains resulted in receptor complexes that failed to incorporate HSP90. Chen and Smith (1998) concluded that HOP acts as an adaptor that directs HSP90 to preexisting HSP70-progesterone receptor complexes.
By mutating the TPR regions of yeast Sti1, Song and Masison (2005) identified separate domains involved in the regulation of Hsp70 and Hsp90. All Sti1 mutations impaired protein folding, which required both Hsp70 and Hsp90. Human HOP1 complemented a yeast strain lacking Sti1, suggesting conservation of HSP70 and HSP90 regulation.
Arruda-Carvalho et al. (2007) stated that STI1 is an extracellular protein that modulates cell death and differentiation through interaction with prion protein (PRNP; 176640). They treated rat retinal explants with mouse Sti1 or with neutralizing antibody and identified both Prnp-dependent and -independent roles for Sti1 in ganglion and neuroblastic cell death and differentiation.
Canalization, or developmental robustness, is an organism's ability to produce the same phenotype despite genotypic variations and environmental influences. Expression of a gain-of-function allele of Drosophila Kruppel results in misregulation of genes in the fly eye disc and generation of eye outgrowths, which are normally repressed via canalization. Using a fly eye outgrowth assay, Gangaraju et al. (2011) showed that a protein complex made up of Piwi (see 605571), Hsp83 (HSP90), and Hop was involved in canalization. The results suggested that canalization may involve Hsp83-mediated phosphorylation of Piwi. Gangaraju et al. (2011) concluded that the eye outgrowth phenotype is a defect in epigenetic silencing of a normally suppressed genotype.
Scheufler et al. (2000) reported the crystal structures of the N-terminal TPR domain (TPR1) of HOP in the presence of a bound peptide consisting of the C-terminal 12 amino acids of HSC70 and of a C-terminal domain (TPR2A) of HOP in complex with a peptide representing the 5 C-terminal residues of HSP90. The structures provided insight into how TPR domain cochaperones specifically recognize HSP70 and HSP90 proteins and explained the conservation of the EEVD motif in all HSP70 and HSP90 family members known to interact with TPR proteins.
The International Radiation Hybrid Mapping Consortium mapped the STIP1 gene to 11q13 (stSG137).
Arruda-Carvalho, M., Njaine, B., Silveira, M. S., Linden, R., Chiarini, L. B. Hop/STI1 modulates retinal proliferation and cell death independent of PrPC. Biochem. Biophys. Res. Commun. 361: 474-480, 2007. [PubMed: 17651690] [Full Text: https://doi.org/10.1016/j.bbrc.2007.07.038]
Chen, S., Smith, D. F. Hop as an adaptor in the heat shock protein 70 (Hsp70) and Hsp90 chaperone machinery. J. Biol. Chem. 273: 35194-35200, 1998. [PubMed: 9857057] [Full Text: https://doi.org/10.1074/jbc.273.52.35194]
Gangaraju, V. K., Yin, H., Weiner, M. M., Wang, J., Huang, X. A., Lin, H. Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation. Nature Genet. 43: 153-158, 2011. [PubMed: 21186352] [Full Text: https://doi.org/10.1038/ng.743]
Honore, B., Leffers, H., Madsen, P., Rasmussen, H. H., Vandekerckhove, J., Celis, J. E. Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1. J. Biol. Chem. 267: 8485-8491, 1992. [PubMed: 1569099]
Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., Bartunik, H., Hartl, F. U., Moarefi, I. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101: 199-210, 2000. [PubMed: 10786835] [Full Text: https://doi.org/10.1016/S0092-8674(00)80830-2]
Song, Y., Masison, D. C. Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). J. Biol. Chem. 280: 34178-34185, 2005. [PubMed: 16100115] [Full Text: https://doi.org/10.1074/jbc.M505420200]