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    The endoplasmic reticulum-associated protein, OS-9, behaves as a lectin in targeting the immature calcium-sensing receptor

    Access Status
    Open access via publisher
    Authors
    Ward, B.
    Rea, S.
    Magno, A.
    Pedersen, B.
    Brown, S.
    Mullin, S.
    Arulpragasam, Ajanthy
    Ingley, E.
    Conigrave, A.
    Ratajczak, T.
    Date
    2017
    Type
    Journal Article
    
    Metadata
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    Citation
    Ward, B. and Rea, S. and Magno, A. and Pedersen, B. and Brown, S. and Mullin, S. and Arulpragasam, A. et al. 2017. The endoplasmic reticulum-associated protein, OS-9, behaves as a lectin in targeting the immature calcium-sensing receptor. Journal of Cellular Physiology. 233 (1): pp. 38–56.
    Source Title
    Journal of Cellular Physiology
    DOI
    10.1002/jcp.25957
    ISSN
    0021-9541
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/53988
    Collection
    • Curtin Research Publications
    Abstract

    The mechanisms responsible for the processing and quality control of the calcium-sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two-hybrid screen of the CaSR C-terminal tail (residues 865-1078), we identified osteosarcoma-9 (OS-9) protein as a binding partner. OS-9 is an ER-resident lectin that targets misfolded glycoproteins to the ER-associated degradation (ERAD) pathway through recognition of specific N-glycans by its mannose-6-phosphate receptor homology (MRH) domain. We show by confocal microscopy that the CaSR and OS-9 co-localize in the ER in COS-1 cells. In immunoprecipitation studies with co-expressed OS-9 and CaSR, OS-9 specifically bound the immature form of wild-type CaSR in the ER. OS-9 also bound the immature forms of a CaSR C-terminal deletion mutant and a C677A mutant that remains trapped in the ER, although binding to neither mutant was favored over wild-type receptor. OS-9 binding to immature CaSR required the MRH domain of OS-9 indicating that OS-9 acts as a lectin most likely to target misfolded CaSR to ERAD. Our results also identify two distinct binding interactions between OS-9 and the CaSR, one involving both C-terminal domains of the two proteins and the other involving both N-terminal domains. This suggests the possibility of more than one functional interaction between OS-9 and the CaSR. When we investigated the functional consequences of altered OS-9 expression, neither knockdown nor overexpression of OS-9 was found to have a significant effect on CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation.

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