Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE-RF

Merlin, the neurofibromatosis 2 tumor suppressor protein, has two major iso forms with alternate C termini and is related to the ERM (ezrin, radixin, m oesin) proteins. Regulation of the ERMs involves intramolecular and/or inte rmolecular head-to-tail associations between family members. We have determ ined whether merlin undergoes similar interactions, and our findings indica te that the C terminus of merlin isoform 1 is able to associate with its N- terminal domain in a head-to-tail fashion. However, the C terminus of isofo rm 2 lacks this property. Similarly, the N terminus of merlin can also asso ciate with C terminus of moesin, We have also explored the effect of merlin self-association on binding to the regulatory cofactor of Na+-H+ exchanger (NHE-RF), an interacting protein for merlin and the ERMs, Merlin isoform 2 captures more NHE-RF than merlin isoform 1 in affinity binding assays, sug gesting that in full-length merlin isoform 1, the NHE-RF binding site is ma sked because of the self-interactions of merlin. Treatment with a phospholi pid known to decrease self-association of ERMs enhances the binding of merl in isoform 1 to NHE-RF, Thus, although isoform 1 resembles the ERM proteins , which transition between inactive (closed) and active (open) states, isof orm 2 is distinct, existing only in the active (open) state and presumably constitutively more available for interaction with other protein partners.