Pavsic, Miha; Ilc, Gregor; Vidmar, Tilen; Plavec, Janez; Lenarcic, Brigita
The cytosolic tail of the tumor marker protein Trop2-a structural switch triggered by phosphorylation
SCIENTIFIC REPORTS, 5 Art. No. 10324, MAY 18 2015

Trop(2) is a transmembrane signaling glycoprotein upregulated in stem and carcinoma cells. Proliferation-enhancing signaling involves regulated intramembrane proteolytic release of a short cytoplasmic fragment, which is later engaged in a cytosolic signaling complex. We propose that Trop(2) function is modulated by phosphorylation of a specific serine residue within this cytosolic region (Ser(303)), and by proximity effects exerted on the cytosolic tail by Trop(2) dimerization. Structural characterization of both the transmembrane (Trop(2)TM) and cytosolic regions (Trop(2)IC) support this hypothesis, and shows that the central region of Trop(2)IC forms an alpha-helix. Comparison of NMR structures of non-phosphorylated and phosphorylated forms suggest that phosphorylation of Trop(2)IC triggers salt bridge reshuffling, resulting in significant conformational changes including ordering of the C-terminal tail. In addition, we demonstrate that the cytosolic regions of two Trop(2) subunits can be brought into close proximity via transmembrane part dimerization. Finally, we show that Ser(303)-phosphorylation significantly affects the structure and accessibility of functionally important regions of the cytosolic tail. These observed structural features of Trop(2) at the membrane-cytosol interface could be important for regulation of Trop(2) signaling activity.


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