STRUCTURE-FUNCTION-RELATIONSHIPS IN THE EZRIN FAMILY AND THE EFFECT OF TUMOR-ASSOCIATED POINT MUTATIONS IN NEUROFIBROMATOSIS-2 PROTEIN

Ezrin, radixin and moesin (ERM proteins) link cell adhesion molecules to the cytoskeleton, modulate cell morphology and cell growth and are involved in Rho-mediated signal transduction. Merlin, the tumor suppre ssor in neurofibromatosis 2, is a diverged member of the ezrin family, but its function is at least partially similar to the ERM proteins. I n the N-domain, the ezrin family belongs to the band 4.1 superfamily, Secondary structure predictions made separately for the ezrin and band 4.1-tyrosine phosphatase families give a similar pattern for the homo logous N-domains, indicating that both families have a similar binding site for the integral membrane proteins. The ct-domain shows a strong coiled-coil prediction, that can be involved in the protein dimerizat ion. The C-terminal actin-binding site in the ERM proteins and the act in-binding helix in the villin headpiece have a common amino acid moti f. In merlin, the published tumor-associated single amino acid mutatio ns in the N-domain are located in the conserved sites, and they affect mainly the predicted helices and strands, indicating that these mutat ions cause the disease primarily by disturbing the protein structure. In the alpha- and C-domains, some of the mutations break the helical s tructures. Some known mutations are observed at a site potentially int eracting with cell adhesion molecules. We will also discuss the implic ations of the evolutionary information and the actin-binding models in the ezrin family. (C) 1998 Elsevier Science B.V. All rights reserved.