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J. Biol. Chem., Vol. 278, Issue 28, 25783-25789, July 11, 2003

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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^*

E. Anne McRobert , Marisa Gallicchio , George Jerums , Mark E. Cooper  and Leon A. Bach  ¶

From the Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia and the Baker Medical Research Institute, Alfred Hospital, Prahran, 3181 Victoria, Australia

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 K_D 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-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.

Received for publication, October 11, 2002 , and in revised form, April 17, 2003.

^* These studies were supported by Juvenile Diabetes Research Foundation International Grant 4-1999-821 and National Health and Medical Research Council of Australia Grant 208940. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Studley Rd., Heidelberg, 3084 Victoria, Australia. Tel.: 61-3-9496-3581; Fax: 61-3-9457-5485, E-mail: l.bach{at}unimelb.edu.au.

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