Structure-Guided Insights into the Function of Merlin in Neurofibromatosis 2 (NF2)

摘要

The tumor suppressor protein merlin interacts with ERM (ezrin, radixin, moesin) proteins and components of cell-cell adherens junctions (AJs) and plays major roles in stabilizing AJs, cell migration and invasion, cell proliferation, contact-mediated cell inhibition, and regulating ligand-mediated cell signaling. Although merlin shares sequence and structural similarity with ERM proteins, and its capacity to bind F-actin and the plasma membrane, it is unique in its function as tumor suppressor. We propose structural characterization of merlin by X-ray crystallography to determine the structure of merlin, its domains, and in complex with its interacting partners. We solved the crystal structure of the human merlin-1 head:tail complex. Surprisingly, unlike other ERM head-tail interactions, the merlin-1 tail provokes dynamic movement and unfurling of the F2 motif of the FERM domain directing dimerization. This dimer formation may control its homeotypic and heterotypic interactions necessary for tumor suppression. Further, crystallizations of merlin and various complexes are in progress.