Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations
Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations
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DOI：
10.1002/(sici)1097-4547(19991201)58:5
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发表时间：
1999-12-01
影响因子：
4.2
通讯作者：
Lu, KH
中科院分区：
文献类型：
--
作者：
Gutmann, DH;Haipek, CA;Lu, KH
神经纤维瘤病2 （NF2）肿瘤抑制基因产物梅林（神经鞘蛋白）形成分子内关联，这是体外和体内负生长调节所必需的。为了建立与其肿瘤抑制功能相关的merlin分子模型，我们进一步表征了merlin分子内折叠。我们现在证明，merlin形成了两种分子内结合，一种是在氨基末端（n项）和羧基末端（c项）之间，另一种是在氨基末端（n项/ n项）本身。N-term/C-term结构域相互作用需要N-term残基302-308与C-term结构域完整的17号外显子（残基580-595）接触。此外，我们证明了N-term/N-term域关联需要N-term/N-term域自交互作用。最后，我们在体外鉴定了NF2患者突变，这些突变显著减少了这些相互作用。基于这些发现，我们提出了一个merlin折叠模型，该模型对其作为肿瘤抑制蛋白的功能至关重要。(C) 1999 Wiley-Liss, Inc。
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. (C) 1999 Wiley-Liss, Inc.