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Drosophila Glycoprotein 93 Is an Ortholog of Mammalian Heat Shock Protein gp96 (grp94, HSP90b1, HSPC4) and Retains Disulfide Bond-Independent Chaperone Function for TLRs and Integrins
Abstract
Mammalian heat shock protein gp96 is an obligate chaperone for multiple integrins and TLRs, the mechanism of which is largely unknown. We have identified gp93 in Drosophila having high sequence homology to gp96. However, no functions were previously attributed to gp93. To determine whether gp93 and gp96 are functionally conserved, we have expressed gp93 in gp96-deficient mouse cells. Remarkably, the Drosophila gp93 is able to chaperone multiple murine gp96 clients including integrins α4, αL, and β2 and TLR2 and TLR9. This observation has led us to examine the structural basis of the chaperone function of gp96 by a close comparison between gp96 and gp93. We report that whereas gp96 undergoes intermolecular disulfide bond formation via Cys138, gp93 is unable to do so due to the absence of a cysteine near the same region. However, abrogation of disulfide bond formation by substituting C with A (C138A) in gp96 via site-directed mutagenesis did not compromise its chaperone function. Likewise, gp93 chaperone ability could not be improved by forcing intermolecular bond formation between gp93 N termini. We conclude that gp93 is the Drosophila ortholog of gp96 and that the chaperone function of the two molecules is conserved. Moreover, gp96 N-terminal disulfide bond formation is not critical for its function, underscoring the importance of N-terminal dimerization via non-disulfide bond-mediated interactions in client protein folding by gp96. Further study of gp96 from an evolutionary angle shall be informative to uncover the detailed mechanism of its chaperone function of client proteins in the secretory pathway.
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The data validated the dependence on gp96 for cell surface expression of integrins α4, αV, αL, and β2, and gp96 independence of integrins β1, α6 and α5.
“Our data was validated by confirming the dependence on gp96 for cell surface expression of integrins α4, αV, αL, and β2,2,3,9,11 and gp96 independence of integrins β1, α6 and α52 (Table 2 and Table S1, Supporting Information).”
Many integrins require chaperoning by gp96, while some α- and β-integrins are gp96 independent.
“While many integrins require chaperoning by gp96, some α- and β-integrins are gp96 independent.2,9”
The reported gp96 dependence of integrins α4, αV, αL, β2 and TLR6 and TLR4, and the lack of dependence of α6 and β1 integrins, were confirmed.
“We confirmed the reported gp96 dependence of integrins α4, αV, αL, β2 and toll-like receptors TLR6 and TLR4, and the lack of dependence of the α6 and β1 integrins.2−4,9,11”
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Cites
Diverse Cellular Functions of the Hsp90 Molecular Chaperone Uncovered Using Systems Approaches
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The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease
Hoter, A., El-Sabban, M. E., & Naim, H. Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092560 · Cited by 693
Weekes, M. P., Antrobus, R., Talbot, S., Hör, S., Simecek, N., Smith, D. L., Bloor, S., Randow, F., & Lehner, P. J. (2012) · Journal of Proteome Research · doi:10.1021/pr201135e · Cited by 82
Metadata
- Authors
- Morales, C., Wu, S., Yang, Y., Hao, B., & Li, Z.
- Affiliations
- Department of Immunology
- Department of Microbial, Molecular and Structural Biology, University of Connecticut School of Medicine , Farmington, CT 06030
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-10
- Volume
- 183
- Issue
- 8
- Pages
- 5121-5128
- ISSN
- 1550-6606
- 0022-1767
- PMC
- PMC2856694
- Cited by
- 32
- References
- 1
- Language
- en
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