Scoles Daniel R, Chen Mercy, Pulst Stefan-M
Division of Neurology, Cedars-Sinai Medical Center, 1145E Medical Tower, 8631 West 3rd Street, Los Angeles, CA 90048, USA.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):366-74. doi: 10.1006/bbrc.2001.6178.
Most benign brain tumors are associated with loss of the Nf2 gene tumor suppressor product schwannomin/merlin. Interactions between schwannomin fragments have given rise to hypotheses of in vivo schwannomin folding and dimerization. Previously, we showed that schwannomin with missense mutations L360P, L535P, and Q538P alters interaction with betaII-spectrin and Hrs. Using yeast two-hybrid tests of interaction, we now show the effects of 11 Nf2 missense mutations on schwannomin self-interaction as well as schwannomin interaction with Hrs isoforms 1 and 2, betaII-spectrin, and p110. Missense mutations L46R and K364I significantly decreased affinity of schwannomin for binding all interacting proteins. The schwannomin L46R mutation may result in a complex conformational change that alters folding and denies betaII-spectrin access to an intact binding site in the C-terminal half of schwannomin. We show that unique inter- and intramolecular interactions occur for schwannomin isoform 2, suggesting that this schwannomin isoform has unique functional properties compared to schwannomin isoform 1.
大多数良性脑肿瘤与Nf2基因肿瘤抑制产物施万蛋白/默林的缺失有关。施万蛋白片段之间的相互作用引发了关于施万蛋白在体内折叠和二聚化的假说。此前，我们发现携带错义突变L360P、L535P和Q538P的施万蛋白会改变与βII-血影蛋白和Hrs的相互作用。通过酵母双杂交相互作用试验，我们现在展示了11种Nf2错义突变对施万蛋白自身相互作用以及施万蛋白与Hrs同工型1和2、βII-血影蛋白和p110相互作用的影响。错义突变L46R和K364I显著降低了施万蛋白与所有相互作用蛋白结合的亲和力。施万蛋白L46R突变可能导致复杂的构象变化，从而改变折叠并阻止βII-血影蛋白进入施万蛋白C端一半的完整结合位点。我们表明，施万蛋白同工型2存在独特的分子间和分子内相互作用，这表明该施万蛋白同工型与施万蛋白同工型1相比具有独特的功能特性。
