期刊
PROTEIN SCIENCE
卷 21, 期 2, 页码 199-210出版社
WILEY
DOI: 10.1002/pro.2003
关键词
G protein coupled receptors (GPCR); adrenomedullin (AM); calcitonin receptor-like receptor (CRLR); receptor activity-modifying protein (RAMP); neovascularization
资金
- RIKEN Structural Genomics/Proteomics Initiative (RSGI)
- National Project on Protein Structural and Functional Analyses
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Grants-in-Aid for Scientific Research [22570175] Funding Source: KAKEN
The calcitonin receptor-like receptor (CRLR), a class B GPCR, forms a heterodimer with receptor activity-modifying protein 2 (RAMP2), and serves as the adrenomedullin (AM) receptor to control neovascularization, while CRLR and RAMP1 form the calcitonin gene-related peptide (CGRP) receptor. Here, we report the crystal structures of the RAMP2 extracellular domain alone and in the complex with the CRLR extracellular domain. The CRLRRAMP2 complex exhibits several intermolecular interactions that were not observed in the previously reported CRLRRAMP1 complex, and thus the shape of the putative ligand-binding pocket of CRLRRAMP2 is distinct from that of CRLRRAMP1. The CRLRRAMP2 interactions were confirmed for the full-length proteins on the cell surface by site-specific photo-crosslinking. Mutagenesis revealed that AM binding requires RAMP2 residues that are not conserved in RAMP1. Therefore, the differences in both the shapes and the key residues of the binding pocket are essential for the ligand specificity.
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