Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes.
Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes.
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DOI：
10.1074/jbc.m109.071910
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发表时间：
2010-01-29
期刊：
影响因子：
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通讯作者：
Shackleton S
中科院分区：
文献类型：
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作者：
Haque F;Mazzeo D;Patel JT;Smallwood DT;Ellis JA;Shanahan CM;Shackleton S
哺乳动物中由SUN结构域和nesprin蛋白组成的核膜（NE）LINC复合物在核纤层和细胞骨架之间提供直接连接，这有助于核定位和细胞刚性。SUN 1和SUN 2与核纤层蛋白A相互作用，但核纤层蛋白A仅为SUN 2的NE定位所需，并且尚不清楚SUN 1如何锚定。在这里，我们确定emerin和短nesprin-2亚型作为新的核质结合伙伴的太阳1/2。这些具有不同于核纤层蛋白A结合位点的重叠结合位点。然而，我们证明了SUN 1与核纤层的紧密结合依赖于残基209-228内的短基序，该区域与已知的SUN 1结合伴侣不显著相互作用。此外，SUN 1正确定位于缺乏emerin的细胞中。重要的是，SUN 1 NE定位的主要决定因素尚未确定。我们进一步发现，与核纤层蛋白病Emery-Dreifuss肌营养不良症（EDMD）和Hutchinson-Gilford早衰综合征（HGPS）相关的核纤层蛋白A突变的子集破坏了核纤层蛋白A与SUN 1和SUN 2的相互作用。尽管如此，在来自任一类别患者的细胞系中，SUN 1和SUN 2的NE定位未受损。有趣的是，NE处的SUN 1表达反而在显著比例的HGPS而不是EDMD细胞中增强，并且由于SUN 1与前核纤层蛋白A的优先相互作用而与前核纤层蛋白A积累强烈相关。我们提出，这些不同的扰动核纤层蛋白A-SUN蛋白相互作用可能是EDMD和HGPS突变对核和细胞力学的相反影响的基础。
The nuclear envelope (NE) LINC complex, in mammals comprised of SUN domain and nesprin proteins, provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity. SUN1 and SUN2 interact with lamin A, but lamin A is only required for NE localization of SUN2, and it remains unclear how SUN1 is anchored. Here, we identify emerin and short nesprin-2 isoforms as novel nucleoplasmic binding partners of SUN1/2. These have overlapping binding sites distinct from the lamin A binding site. However, we demonstrate that tight association of SUN1 with the nuclear lamina depends upon a short motif within residues 209–228, a region that does not interact significantly with known SUN1 binding partners. Moreover, SUN1 localizes correctly in cells lacking emerin. Importantly then, the major determinant of SUN1 NE localization has yet to be identified. We further find that a subset of lamin A mutations, associated with laminopathies Emery-Dreifuss muscular dystrophy (EDMD) and Hutchinson-Gilford progeria syndrome (HGPS), disrupt lamin A interaction with SUN1 and SUN2. Despite this, NE localization of SUN1 and SUN2 is not impaired in cell lines from either class of patients. Intriguingly, SUN1 expression at the NE is instead enhanced in a significant proportion of HGPS but not EDMD cells and strongly correlates with pre-lamin A accumulation due to preferential interaction of SUN1 with pre-lamin A. We propose that these different perturbations in lamin A-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.