Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation
Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation
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DOI：
10.1523/jneurosci.0591-15.2015
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发表时间：
2015-08-26
影响因子：
5.3
通讯作者：
Hempstead, Barbara L.
中科院分区：
文献类型：
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作者：
Anastasia, Agustin;Barker, Phillip A.;Hempstead, Barbara L.
p75 神经营养蛋白受体 (p75(NTR)) 是一种多功能受体，参与神经系统中的许多关键过程，从细胞凋亡到突触可塑性和形态事件。它是肿瘤坏死因子受体 (TNFR) 超家族的成员，其成员发生三聚寡聚化。有趣的是，p75(NTR) 与二聚体配体（即前神经营养蛋白或成熟神经营养蛋白）相互作用，但介导 p75(NTR) 信号传导的几种细胞内接头是三聚体（即 TNFR 相关因子 6 或 TRAF6）。因此，活性受体信号传导单元仍然不确定。为了鉴定功能性受体复合物，我们结合生化技术在体外和小鼠脑组织中评估了其寡聚化。我们发现p75(NTR)最丰富的同型排列是三聚体，并且单体和三聚体在细胞表面共存。有趣的是，在生长锥回缩功能测定中，配体独立或配体依赖性 p75(NTR) 激活不需要三聚体。然而，单体能够在神经元中诱导急性形态效应。我们认为 p75(NTR) 的激活受其寡聚状态及其表达水平的调节。这些结果表明 p75(NTR) 的寡聚状态赋予不同的反应，并为该受体在神经系统中的多样化和矛盾的作用提供了解释。
The p75 neurotrophin receptor (p75(NTR)) is a multifunctional receptor that participates in many critical processes in the nervous system, ranging from apoptosis to synaptic plasticity and morphological events. It is a member of the tumor necrosis factor receptor (TNFR) superfamily, whose members undergo trimeric oligomerization. Interestingly, p75(NTR) interacts with dimeric ligands (i.e., proneurotrophins or mature neurotrophins), but several of the intracellular adaptors that mediate p75(NTR) signaling are trimeric (i.e., TNFR-associated factor 6 or TRAF6). Consequently, the active receptor signaling unit remains uncertain. To identify the functional receptor complex, we evaluated its oligomerization in vitro and in mice brain tissues using a combination of biochemical techniques. We found that the most abundant homotypic arrangement for p75(NTR) is a trimer and that monomers and trimers coexist at the cell surface. Interestingly, trimers are not required for ligand-independent or ligand-dependent p75(NTR) activation in a growth cone retraction functional assay. However, monomers are capable of inducing acute morphological effects in neurons. We propose that p75(NTR) activation is regulated by its oligomerization status and its levels of expression. These results indicate that the oligomeric state of p75(NTR) confers differential responses and offers an explanation for the diverse and contradictory actions of this receptor in the nervous system.