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A critical role for the short intracellular C terminus in receptor activity-modifying protein function

Udawela, Madhara, Christopoulos, George, Morfis, Maria, Christopoulos, Arthur, Ye, Siying, Tilakaratne, Nanda and Sexton, Patrick M. 2006, A critical role for the short intracellular C terminus in receptor activity-modifying protein function, Molecular pharmacology, vol. 70, no. 5, pp. 1750-1760, doi: 10.1124/mol.106.024257.

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Title A critical role for the short intracellular C terminus in receptor activity-modifying protein function
Author(s) Udawela, Madhara
Christopoulos, George
Morfis, Maria
Christopoulos, Arthur
Ye, Siying
Tilakaratne, Nanda
Sexton, Patrick M.
Journal name Molecular pharmacology
Volume number 70
Issue number 5
Start page 1750
End page 1760
Publisher American Society for Pharmacology and Experimental Therapeutics
Place of publication Bethesda, Md.
Publication date 2006-11
ISSN 0026-895X
1521-0111
Summary Receptor activity-modifying proteins (RAMPs) interact with and modify the behavior of the calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR). We have examined the contribution of the short intracellular C terminus, using constructs that delete the last eight amino acids of each RAMP. C-Terminal deletion of individual RAMPs had little effect on the signaling profile induced when complexed with CLR in COS-7 or human embryonic kidney (HEK)293 cells. Likewise, confocal microscopy revealed each of the mutant RAMPs translocated hemagglutinin-tagged CLR to the cell surface. In contrast, a pronounced effect of RAMP C-terminal truncation was seen for RAMP/CTRa complexes, studied in COS-7 cells, with significant attenuation of amylin receptor phenotype induction that was stronger for RAMP1 and -2 than RAMP3. The loss of amylin binding upon C-terminal deletion could be partially recovered with overexpression of Gαs, suggesting an impact of the RAMP C terminus on coupling of G proteins to the receptor complex. In HEK293 cells the c-Myc-RAMP1 C-terminal deletion mutant showed high receptor-independent cell surface expression; however, this construct showed low cell surface expression when expressed alone in COS-7 cells, indicating interaction of RAMPs with other cellular components via the C terminus. This mutant also had reduced cell surface expression when coexpressed with CTR. Thus, this study reveals important functionality of the RAMP C-terminal domain and identifies key differences in the role of the RAMP C terminus for CTR versus CLR-based receptors.
Language eng
DOI 10.1124/mol.106.024257
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, The American Society for Pharmacology and Experimental Therapeutics
Persistent URL http://hdl.handle.net/10536/DRO/DU:30040951

Document type: Journal Article
Collection: School of Medicine
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