Abstract
Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region and a C-terminal domain that binds to the FERM domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. These conformational transitions are regulated by both phosphorylation and phosphoinositide binding. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay and found that Merlin dimerizes via a FERM-FERM interaction in a parallel orientation that requires an uncovered N-terminus and the first 18 amino acids of the FERM domain. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Dimerization requires an open conformation, is inhibited by phosphorylation at serine 518 and is enhanced by PIP2 binding. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with significant implications for the development of therapies designed to compensate for Merlin loss.
Competing Interest Statement
The authors have declared no competing interest.
