Structural distinctions in BMPs underlie divergent signaling in spinal neurons.
Structural distinctions in BMPs underlie divergent signaling in spinal neurons.
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DOI：
10.1186/1749-8104-7-16
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发表时间：
2012-05-04
影响因子：
3.6
通讯作者：
Dodd J
中科院分区：
文献类型：
--
作者：
Perron JC;Dodd J
在脊髓背侧神经元和单核细胞中，骨形态发生蛋白(BMP)7激活了不同的转导通路，一条导致诱导规范，另一条导致轴突定向和趋化。Bmp7的诱导也受到密切相关的Bmp6的刺激，通过Smad级联起作用，导致核信号，并且不是BMPR亚单位选择性的。定向是由BMP7引起的，而不是由Bmp6引起的，通过依赖于PI3K的细胞骨架激活，由II型BMPR，ActRIIA和BMPRII介导，并且不依赖于Smad级联。这些反应可以同时被刺激，这表明BMP7，而不是BMP6，可以选择性地激活参与不同路径的BMPR亚单位。尽管对选定的BMP/BMPR界面的结构和生化分析已经确定了相互作用的关键区域，但这些区域如何转化为相关BMP的功能尚不清楚。为了确定BMP7不同活性的机制以及BMP7和BMP6在脊髓发育中的不同性质，我们对BMPs进行了家族范围的结构/功能分析，并使用这些信息来预测和测试BMPs中可能通过与BMPRs相互作用来控制激动剂特性的位置，特别是BMP定位轴突的能力。我们证明，虽然所有的骨形态发生蛋白都可以诱导背侧神经元，但也有选择性地定向轴突或引起生长锥塌陷。BMP的定向程度不能通过与其他BMP的总体蛋白质相似性来预测，但将强定向和弱定向BMP的序列与非定向BMP6的序列进行比较，发现了BMP中的三个候选位置，在这些位置上，氨基酸残基可能赋予或阻碍定向能力。残基交换分析已经确定了Bmp6中的一个残基Gln48，它阻止了轴突定向能力。将Gln48替换为BMPs定向亚集中同等残基位置上的任何氨基酸，可使Bmp6具有定向活性。相反，将Gln48替换为BMP7会降低定位能力。BMP的诱导能力不受这些残基交换的影响。结果表明，BMP6中Gln48残基的存在对BMP/BMPR相互作用具有结构上的抑制作用，这种相互作用导致细胞内信号的激活，从而导致轴突定向。此外，由于BMP7中的48个残基和BMP2中的相应残基对于II型BMPR结合是重要的，我们的结果为从机制上理解BMPs在脊髓发育中的不同活动提供了基础。
In dorsal spinal neurons and monocytes, bone morphogenetic protein (BMP)7 activates distinct transduction pathways, one leading to inductive specification and the other to axon orientation and chemotaxis. BMP7-evoked induction, also stimulated by the closely related BMP6, acts through a Smad cascade, leading to nuclear signaling, and is not BMPR subunit selective. Orientation is evoked by BMP7, but not by BMP6, through PI3K-dependent cytoskeletal activation mediated by the type II BMPRs, ActRIIA and BMPRII and is independent of the Smad cascade. The responses can be stimulated concurrently and suggest that BMP7, but not BMP6, can selectively activate BMPR subunits that engage the divergent paths. Although structural and biochemical analyses of selected BMP/BMPR interfaces have identified key regions of interaction, how these translate into function by related BMPs is poorly understood. To determine the mechanisms underlying the distinct activities of BMP7 and the disparate properties of BMP7 and BMP6 in spinal cord development, we have performed a family-wide structure/function analysis of BMPs and used the information to predict and test sites within BMPs that may control agonist properties, in particular the ability of a BMP to orient axons, through interactions with BMPRs. We demonstrate that whereas all BMPs can induce dorsal neurons, there is selectivity in the ability also to orient axons or evoke growth cone collapse. The degree to which a BMP orients is not predictable by overall protein similarity with other BMPs but comparison of sequences of potent and weakly orienting BMPs with that of the non-orienting BMP6 revealed three candidate positions within the BMPs at which the amino acid residues may confer or obstruct orienting ability. Residue swapping analysis has identified one residue, Gln48 in BMP6, that blocks axon orienting ability. Replacing Gln48 with any of the amino acids present at the equivalent residue position in the orienting subset of BMPs confers orienting activity on BMP6. Conversely, swapping Gln48 into BMP7 reduces orienting ability. The inductive capacity of the BMPs was unchanged by these residue swaps. The results suggest that the presence of the Gln48 residue in BMP6 is structurally inhibitory for BMP/BMPR interactions that result in the activation of intracellular signaling, leading to axon orientation. Moreover, since residue 48 in BMP7 and the corresponding residue in BMP2 are important for type II BMPR binding, our results provide a basis for a mechanistic understanding of the diverse activities of BMPs in spinal cord development.
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影响因子：
5.4
作者：
Heinecke K;Seher A;Schmitz W;Mueller TD;Sebald W;Nickel J
通讯作者：
Nickel J
DOI：
10.1083/jcb.109.4.1621
发表时间：
1989-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Goslin K;Birgbauer E;Banker G;Solomon F
通讯作者：
Solomon F
影响因子：
16.2
作者：
DODD, J;MORTON, SB;JESSELL, TM
通讯作者：
JESSELL, TM
DOI：
10.1073/pnas.0602558103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Allendorph, George P.;Vale, Wylie W.;Choe, Senyon
通讯作者：
Choe, Senyon
影响因子：
4.8
作者：
Nohe, A;Hassel, S;Knaus, P
通讯作者：
Knaus, P