Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations

The neurofibromatosis 2 (NF2) tumor suppressor gene product, merlin (schwan nomin) forms an intramolecular association that is required for negative gr owth regulation in vitro and in vivo. In an effort to develop a molecular m odel for merlin relevant to its tumor suppressor function, we further chara cterized merlin intramolecular folding. We now demonstrate that merlin form s two intramolecular associations, one between the amino terminal (N-term) domain and the carboxyl terminal (C-term) domain and another within the ami no terminal domain (N-term/N-term) itself. The N-term/C-term domain interac tion requires contact between residues 302-308 in the N-term and an intact exon 17 (residues 580-595) in the C-term domain. In addition, we demonstrat e that the N-term/N-term domain self-interaction is required for N-term/C-t erm domain association. Lastly, we identify NF2 patient mutations that dram atically reduce each of these interactions in vitro. Based on these finding s, we propose a model for merlin folding critical to its ability to functio n as a tumor suppressor protein. (C) 1999 Wiley-Liss, Inc.