Journal
BIOCHEMICAL JOURNAL
Volume 473, Issue -, Pages 661-672Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20151041
Keywords
bone morphogenetic protein; electrostatic interaction; N-glycosylation; peripheral membrane protein; SCUBE1; signalling
Categories
Funding
- Academia Sinica
- Ministry of Science and Technology of Taiwan [VTA105-T-3-1, MOST 105-0210-01-13-01, MOST 104-0210-01-09-02, 104-2320-B-001-011-MY3, 103-2325-B-001-004, 102-2320-B-001-015-MY3]
- National Science Council [102-2321-B-001-038]
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SCUBE1 (S1), a secreted and membrane-bound glycoprotein, has a modular protein structure composed of an N-terminal signal peptide sequence followed by nine epidermal growth factor (EGF)-like repeats, a spacer region and three cysteine-rich (CR) motifs with multiple potential N-linked glycosylation sites, and one CUB domain at the C-terminus. Soluble S1 is a biomarker of platelet activation but an active participant of thrombosis via its adhesive EGF-like repeats, whereas its membrane-associated form acts as a bone morphogenetic protein (BMP) co-receptor in promoting BMP signal activity. However, the mechanism responsible for the membrane tethering and the biological importance of N-glycosylation of S1 remain largely unknown. In the present study, molecular mapping analysis identified a polycationic segment (amino acids 501-550) in the spacer region required for its membrane tethering via electrostatic interactions possibly with the anionic heparan sulfate proteoglycans. Furthermore, deglycosylation by peptide N-glycosidase F treatment revealed that N-glycans within the CR motif are essential for membrane recruitment through lectin-mediated surface retention. Injection of mRNA encoding zebrafish wildtype but not N-glycan-deficient scube1 restores the expression of haematopoietic and erythroid markers (scl and gata1) in scube1-knockdown embryos. We describe novel mechanisms in targeting S1 to the plasma membrane and demonstrate that N-glycans are required for S1 functions during primitive haematopoiesis in zebrafish.
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