The neurofibromatosis 2 (NF2) tumor suppressor gene product, merlin (schwannomin) forms an intramolecular association that is required for negative growth regulation in vitro and in vivo. In an effort to develop a molecular model for merlin relevant to its tumor suppressor function, we further characterized merlin intramolecular folding. We now demonstrate that merlin forms two intramolecular associations, one between the amino terminal (N-term) domain and the carboxyl terminal (C-term) domain and another within the amino terminal domain (N-term/N-term) itself. The N-term/C-term domain interaction 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 demonstrate that the N-term/N-term domain self-interaction is required for N-term/C-term domain association. Lastly, we identify NF2 patient mutations that dramatically reduce each of these interactions in vitro. Based on these findings, we propose a model for merlin folding critical to its ability to function as a tumor suppressor protein. Copyright 1999 Wiley-Liss, Inc.