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Direct Determination Of Multiple Ligand Interactions With The Extracellular Domain Of The Calcium Sensing Receptor, Chen Zhang, You Zhuo, Heather A. Moniz, Shuo Wang, Kelley W. Moremen, James H. Prestegard, Edward M. Brown, Jenny J. Yang
Direct Determination Of Multiple Ligand Interactions With The Extracellular Domain Of The Calcium Sensing Receptor, Chen Zhang, You Zhuo, Heather A. Moniz, Shuo Wang, Kelley W. Moremen, James H. Prestegard, Edward M. Brown, Jenny J. Yang
Chemistry Faculty Publications
Numerous in vivo functional studies have indicated that the dimeric extracellular domain (ECD) of the CaSR plays a crucial role in regulating Ca2+ homeostasis by sensing Ca2+ and L-Phe. However, direct interaction of Ca2+ and Phe with the receptor’s ECD and the resultant impact on its structure and associated conformational changes have been hampered by the large size of the ECD, its high degree of glycosylation, and the lack of biophysical methods to monitor weak interactions in solution. In the present study, we purified the glycosylated extracellular domain of CaSR (ECD) (residues 20~612), containing either complex or high mannose N-glycan …
Identification Of An L-Phenylalanine Binding Site Enhancing The Cooperative Responses Of The Calcium Sensing Receptor To Calcium, Chen Zhang, Yun Huang, Yusheng Jiang, Nagaraju Mulpuri, Ling Wei, Donald Hamelberg, Edward M. Brown, Jenny J. Yang
Identification Of An L-Phenylalanine Binding Site Enhancing The Cooperative Responses Of The Calcium Sensing Receptor To Calcium, Chen Zhang, Yun Huang, Yusheng Jiang, Nagaraju Mulpuri, Ling Wei, Donald Hamelberg, Edward M. Brown, Jenny J. Yang
Chemistry Faculty Publications
Functional positive cooperative activation of the extracellular calcium ([Ca2+]o)-sensing receptor (CaSR), a member of the family C G protein-coupled receptors (GPCRs), by [Ca2+]o or amino acids elicits intracellular Ca2+ ([Ca2+]i) oscillations. Here, we report the central role of predicted Ca2+-binding Site 1 within the hinge region of the extracellular domain (ECD) of CaSR and its interaction with other Ca2+-binding sites within the ECD in tuning functional positive homotropic cooperativity caused by changes in [Ca2+]o. Next, we identify an adjacent L-Phe-binding pocket that is responsible for positive heterotropic cooperativity between [Ca2+]o and L- Phe in eliciting CaSR-mediated [Ca2+]i oscillations. The hetero-communication …