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Solution structure and amino acid residues of C‐terminal RAGE (ctRAGE) involved in binding to Dia‐1 FH1 and its signaling
Author(s) -
RAI VIVEK,
Maldonado Andres,
Yan ShiFang,
Schmidt Ann Marie,
Shekhtman Alexander
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.121.4
Subject(s) - rage (emotion) , microbiology and biotechnology , signal transduction , cytoplasm , phosphorylation , receptor , chemistry , biology , biochemistry , neuroscience
The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule that binds distinct ligands implicated in diabetes and inflammation. RAGE‐dependent signal transduction is critically dependent on its short cytoplasmic domain and our recent work revealed that FH1 domain of Dia‐1 binds to cytoplasmic tail (ct)RAGE. However, the cytoplasmic domain structure and pathways by which RAGE signals through mDia1 have yet to be fully explored. Here we present the solution structure of RAGE cytoplasmic domain and identify the Dia1‐ctRAGE interaction surface. Using in‐vitro NMR binding studies, we show that two amino acids, which are part of the Dia1‐ctRAGE interaction surface, R5 and Q6 of ctRAGE are essential for interactions with Dia1. To confirm the Dia1‐ctRAGE interaction surface we generated the ctRAGE double mutant where residues R5 and Q6 were changed to alanine to create R5AQ6A‐ctRAGE and tested the hypothesis that RAGE mediated signaling proceeds via these residues. mDia‐1 FH1 domain interacts with ctRAGE and is essential for ERK, AKT, JNK activation and GSK3beta phosphorylation signaling triggered by RAGE ligands. Our findings present the ctRAGE structure and establish a novel mechanism by which an extracellular signal initiated by RAGE ligands regulates RAGE signaling in a manner requiring Dia‐1.