Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/9489
Title: The amino-terminal domains of the ezrin, radixin, and moesin (ERM) proteins bind advanced glycation end products, an interaction that may play a role in the development of diabetic complications.
Authors: McRobert, E Anne;Gallicchio, Marisa;Jerums, George;Cooper, Mark E;Bach, Leon A
Affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia.
Issue Date: 6-May-2003
Citation: The Journal of Biological Chemistry 2003; 278(28): 25783-9
Abstract: The presence of advanced glycation end products (AGEs) formed because of hyperglycemia in diabetic patients has been strongly linked to the development of diabetic complications and disturbances in cellular function. In this report, we describe the isolation and identification of novel AGE-binding proteins from diabetic rat kidneys. The proteins were purified by cation exchange and AGE-modified bovine serum albumin (AGE-BSA) affinity chromatography. NH2-terminal and internal sequencing identified the proteins as the NH2-terminal domains of ezrin, radixin, and moesin (ERM proteins). Using BIAcore biosensor analysis, human N-ezrin-(1-324) bound to immobilized AGE-BSA with a KD of 5.3 +/- 2.1 x 10 -7 m, whereas full-length ezrin-(1-586) and C-ezrin-(323-586) did not bind. Other glycated proteins such as AGE-RNase, N in -carboxymethyllysine (CML)-BSA, and glycated human serum albumin isolated from hyperglycemic diabetic sera competed with the immobilized AGE-BSA for binding to N-ezrin, but non-glycated BSA and RNase did not. Thus N-ezrin binds to AGEs in a glycation- and concentration-dependent manner. Phosphorylated ezrin plays a crucial role in cell shape changes, cell attachment, and cell adhesion. The effect of AGE-BSA on ezrin function was studied in a tubulogenesis model in which LLC-PK1 cell tubule formation is dependent on phosphorylated ezrin. Addition of AGE-BSA completely inhibited the ability of the cells to produce tubules. Furthermore, in vitro tyrosine phosphorylation of N-ezrin and ezrin was also inhibited by AGE-BSA. These proteins represent a novel family of intracellular binding molecules for glycated proteins and provide a potential new target for therapeutic intervention in the prevention or treatment of diabetic complications.
Internal ID Number: 12734202
URI: http://ahro.austin.org.au/austinjspui/handle/1/9489
DOI: 10.1074/jbc.M210433200
URL: http://www.ncbi.nlm.nih.gov/pubmed/12734202
Type: Journal Article
Subjects: Animals
Binding Sites
Biosensing Techniques
Blood Proteins.chemistry
Blotting, Western
Cattle
Chromatography, Affinity
Cloning, Molecular
Cytoskeletal Proteins.chemistry
Detergents.pharmacology
Diabetes Complications
Diabetes Mellitus.metabolism
Diabetes Mellitus, Experimental
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Glycosylation End Products, Advanced.metabolism
Humans
Kidney.metabolism
Ligands
Lysine.analogs & derivatives.chemistry
Membrane Proteins.chemistry
Microfilament Proteins.chemistry
Phosphoproteins.chemistry
Phosphorylation
Protein Binding
Protein Structure, Tertiary
Rats
Recombinant Proteins.chemistry.metabolism
Serum Albumin.metabolism
Time Factors
Tumor Cells, Cultured
Tyrosine.metabolism
Appears in Collections:Journal articles

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