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Structure-Function Relationships in Merlin, the Product of the NF2 Causal Gene

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Final rept. 10 Sep 2003-9 Sep 2004

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Neurofibromatosis type 2 NF2 is a debilitating, inherited disorder characterized by tumors of the brain and central nervous system. It is caused by the lack of a functional product of the NF2 gene, known as merlin. Merlin serves as a linker protein between the cell membrane and the cytoskeleton. During the tenure of this grant, we used X-ray crystallography to determine the structure of the N-terminal FERM domain of merlin and we analyzed its functional implications. We also investigated structure-function relationships in syntenin, a scaffolding protein that binds to merlin. The structure of the 2nd PDZ tandem of syntenin was determined at 1.9 A resolution, and we also determined the structure of the 2nd PDZ domain of syntenin to 0.73 A, making it one of the highest resolution protein structures determined thus far. Furthermore, the structures of numerous complexes of syntenin with peptide ligands were determined to gain a better understanding of peptide recognition by PDZ domains. This lead to the formulation of the combinatorial model of peptide recognition, which helps explain non-canonical PDZ domain specificities. Biophysical and biochemical techniques were used to characterize the interaction of the PDZ domains with peptides derived from syntenin binding partners including merlin, syndecan, and the interleukin 5 receptor alpha-subunit.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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