The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b

Authors

  • Claudia Zahn,

    1. Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin, Berlin, Germany
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  • Matthias Kaup,

    1. Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin, Berlin, Germany
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  • Regina Fluhrer,

    1. Adolf-Butenandt-Institute of Biochemistry, Ludwig-Maximilians-University, Munich, Germany
    2. DZNE – German Center for Neurodegenerative Diseases, Munich, Germany
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  • Hendrik Fuchs

    Corresponding author
    • Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin, Berlin, Germany
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Correspondence

H. Fuchs, Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany

Fax: +49 30 8445 4152

Tel: +49 30 8445 2559

E-mail: hendrik.fuchs@charite.de

Abstract

The successive events of shedding and regulated intramembrane proteolysis are known to comprise a fundamental biological process of type I and II membrane proteins (e.g. amyloid precursor protein, Notch receptor and pro-tumor necrosis factor-α). Some of the resulting fragments were shown to be involved in important intra- and extracellular signalling events. Although shedding of the human transferrin receptor-1 (TfR1) has been known for > 30 years and soluble TfR1 is an accepted diagnostic marker, the fate of the remaining N-terminal fragment (NTF) remains unknown. In the present study, we demonstrate for the first time that TfR1-NTF is subject to regulated intramembrane proteolysis and, using MALDI-TOF-TOF-MS, we have identified the cleavage site as being located C-terminal from Gly-84. We showed that the resulting C-terminal peptide is extracellularly released after regulated intramembrane proteolysis and it was detected as a monomer with an internal disulfide bridge. We further identified signal peptide peptidase-like 2a and mainly signal peptide peptidase-like 2b as being responsible for the intramembrane proteolysis of TfR1-NTF.

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