期刊
MOLECULAR BIOLOGY OF THE CELL
卷 15, 期 11, 页码 5012-5020出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E04-08-0673
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资金
- NHLBI NIH HHS [T32 HL007781] Funding Source: Medline
- NIAID NIH HHS [AI48585, R01 AI049793, AI49793, R01 AI048585] Funding Source: Medline
- NICHD NIH HHS [HD042598, R01 HD037976, R01 HD042598, HD37976] Funding Source: Medline
- NIDDK NIH HHS [R01 DK037274, DK37274] Funding Source: Medline
Pro bone morphogenetic protein-4 (BMP-4) is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site). Previous studies have shown that S2 cleavage regulates the activity and signaling range of mature BMP-4, but the mechanism by which this occurs is unknown. Here, we show that the pro- and mature domains of BMP-4 remain noncovalently associated after S1 cleavage, generating a complex that is targeted for rapid degradation. Degradation requires lysosomal and proteosomal function and is enhanced by interaction with heparin sulfate proteoglycans. Subsequent cleavage at the S2 site liberates mature BMP-4 from the prodomain, thereby stabilizing the protein. We also show that cleavage at the S2, but not the S1 site, is enhanced at reduced pH, consistent with the possibility that the two cleavages occur in distinct subcellular compartments. Based on these results, we propose a model for how cleavage at the upstream site regulates the activity and signaling range of mature BMP-4 after it has been released from the prodomain.
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