Volume 17, No 12, Dec 2007
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 17 Issue 12, December 2007: 985-998
ORIGINAL ARTICLES
The transmembrane domain of TACE regulates protein ectodomain shedding
Xiaojin Li1,*, Liliana Pérez1,2,3,*, Zui Pan1 and Huizhou Fan1
1Department of Physiology and Biophysics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, NJ 08854, USA
2Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA
3Molecular BioSciences Graduate Program, Rutgers The State University of New Jersey, Piscataway, NJ 08854, USA
Correspondence: Huizhou Fan(fanhu@umdnj.edu)
Numerous membrane proteins are cleaved by tumor necrosis factor-α converting enzyme (TACE), which causes the release of their ectodomains. An ADAM (a disintegrin and metalloprotease domain) family member, TACE contains several noncatalytic domains whose roles in ectodomain shedding have yet to be fully resolved. Here, we have explored the function of the transmembrane domain (TM) of TACE by coupling molecular engineering and functional analysis. A TM-free TACE construct that is anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI)-binding polypeptide failed to restore shedding of transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF-α) and L-selectin in cells lacking endogenous TACE activity. Substitution of the TACE TM with that of the prolactin receptor or platelet-derived growth factor receptor (PDGFR) also resulted in severe loss of TGF-α shedding, but had no effects on the cleavage of TNF-α and L-selectin. Replacement of the TM in TGF-α with that of L-selectin enabled TGF-α shedding by the TACE mutants carrying the TM of prolactin receptor and PDGFR. Taken together, our observations suggest that anchorage of TACE to the lipid bilayer through a TM is required for efficient cleavage of a broad spectrum of substrates, and that the amino-acid sequence of TACE TM may play a role in regulatory specificity among TACE substrates.
Cell Research (2007) 17: 985-998. doi: 10.1038/cr.2007.98; published online 27 November 2007
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