Hierarchical organization and genetically separable subfamilies of PSD95 postsynaptic supercomplexes.
Hierarchical organization and genetically separable subfamilies of PSD95 postsynaptic supercomplexes.
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DOI：
10.1111/jnc.14056
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发表时间：
2017-08
影响因子：
4.7
通讯作者：
Grant SGN
中科院分区：
文献类型：
--
作者：
Frank RAW;Zhu F;Komiyama NH;Grant SGN
PSD 95是突触能突触中丰富的突触后支架蛋白，其组装成由包括神经递质受体、离子通道和粘附蛋白在内的80多种蛋白质组成的超复合物。这些不同的成分如何在体内组织成PSD 95超复合物还知之甚少。在这里，我们结合内源性基因标记、靶向突变和定量生化测定，剖析了小鼠中的超复合物。产生具有两个不同基因标签的复合杂合小鼠，每个Psd 95等位基因上一个，表明每个含有约1.5 MDa Psd 95的超复合物平均含有两个Psd 95分子。用相同的Flag标签对内源性GluN 1和PSD 95进行基因标记，发现含有N-甲基D-天冬氨酸受体（NMDAR）的超复合物仅占PSD 95超复合物总数的3%，这表明还有许多其他亚型。为了确定这种不同PSD 95超复合物的扩展群体是否使用遗传定义的机制来指定它们的组装，我们测试了五种靶向小鼠突变对已知PSD 95相互作用子Kir2.3、Arc、IQsec 2/BRAG 1和Adam 22组装的影响。出乎意料的是，一些突变是高度选择性的，而另一些突变则引起了广泛的破坏，这表明PSD 95相互作用蛋白质分层组织成不同的~1.5 MDa超复合物亚家族，包括Kir2.3-NMDAR离子通道-通道超复合物亚群。Kir2.3-NMDAR离子通道-通道超复合物被发现在解剖学上局限于特定的大脑区域。这些数据提供了新的洞察机制，支配突触后超复合物的成分和突触类型的多样性。 阅读第500页上这篇文章的编辑摘要。 本期封面图片：doi。10.1111/jnc.13811。
PSD95 is an abundant postsynaptic scaffold protein in glutamatergic synapses that assembles into supercomplexes composed of over 80 proteins including neurotransmitter receptors, ion channels and adhesion proteins. How these diverse constituents are organized into PSD95 supercomplexes in vivo is poorly understood. Here, we dissected the supercomplexes in mice combining endogenous gene‐tagging, targeted mutations and quantitative biochemical assays. Generating compound heterozygous mice with two different gene‐tags, one on each Psd95 allele, showed that each ~1.5 MDa PSD95‐containing supercomplex contains on average two PSD95 molecules. Gene‐tagging the endogenous GluN1 and PSD95 with identical Flag tags revealed N‐methyl D‐aspartic acid receptors (NMDARs) containing supercomplexes that represent only 3% of the total population of PSD95 supercomplexes, suggesting there are many other subtypes. To determine whether this extended population of different PSD95 supercomplexes use genetically defined mechanisms to specify their assembly, we tested the effect of five targeted mouse mutations on the assembly of known PSD95 interactors, Kir2.3, Arc, IQsec2/BRAG1 and Adam22. Unexpectedly, some mutations were highly selective, whereas others caused widespread disruption, indicating that PSD95 interacting proteins are organized hierarchically into distinct subfamilies of ~1.5 MDa supercomplexes, including a subpopulation of Kir2.3‐NMDAR ion channel‐channel supercomplexes. Kir2.3‐NMDAR ion channel‐channel supercomplexes were found to be anatomically restricted to particular brain regions. These data provide new insight into the mechanisms that govern the constituents of postsynaptic supercomplexes and the diversity of synapse types. Read the Editorial Highlight for this article on page 500. Cover Image for this issue: doi. 10.1111/jnc.13811.
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影响因子：
4.6
作者：
Broadhead MJ;Horrocks MH;Zhu F;Muresan L;Benavides-Piccione R;DeFelipe J;Fricker D;Kopanitsa MV;Duncan RR;Klenerman D;Komiyama NH;Lee SF;Grant SG
通讯作者：
Grant SG
影响因子：
9.9
作者：
Fernandez, Esperanza;Collins, Mark O.;Uren, Rachel T.;Kopanitsa, Maksym V.;Komiyama, Noboru H.;Croning, Mike D. R.;Zografos, Lysimachos;Armstrong, J. Douglas;Choudhary, Jyoti S.;Grant, Seth G. N.
通讯作者：
Grant, Seth G. N.
影响因子：
4
作者：
Christopherson, KS;Sweeney, NT;Bredt, DS
通讯作者：
Bredt, DS
影响因子：
64.8
作者：
Migaud, M;Charlesworth, P;Grant, SGN
通讯作者：
Grant, SGN
突触后密度的相变是突触复合体和突触可塑性形成的基础。
影响因子：
64.5
作者：
Zeng M;Shang Y;Araki Y;Guo T;Huganir RL;Zhang M
通讯作者：
Zhang M