Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.
Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.
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DOI：
10.1186/1741-7007-7-59
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发表时间：
2009-09-07
期刊：
影响因子：
5.4
通讯作者：
Nickel J
中科院分区：
文献类型：
--
作者：
Heinecke K;Seher A;Schmitz W;Mueller TD;Sebald W;Nickel J
转化生长因子(TGF)β超家族成员通过寡聚两类丝氨酸/苏氨酸激酶受体（称为I型和II型）来转导信号。与大量的配体相比，哺乳动物中仅鉴定出7种I型受体和5种II型受体，这表明配体-受体相互作用存在明显的混杂性。由于给定的配体通常可以与任一亚型的一种以上受体相互作用，因此结合亲和力和特异性的差异对于产生具有不同信号传导特性的不同配体-受体复合物可能很重要。体外相互作用分析显示了两种不同的结合动力学原型，“慢开/慢关”和“快开/快关”。令人惊讶的是，配体对一种亚型受体的结合特异性只有中等程度。从配体的二聚体性质可以看出，由于二价配体-受体相互作用引起的协同结合，与固定化受体的结合表现出强烈的亲和性。为了将这些体外观察结果与体内情况进行比较，我们对采用同源二聚体和异二聚体骨形态发生蛋白2 （BMP2）突变体的全细胞进行了结合研究。有趣的是，通过分别存在一个或两个BMP受体(BMPR)-IA受体链，确定了低亲和力和高亲和力结合位点。这两个位点有助于不同的细胞反应，因为高亲和力位点在低配体浓度下允许快速的瞬态反应，而低亲和力位点促进持续的信号传导，但需要更高的配体浓度。配体与单一高亲和力受体链结合，作为锚定分子并提供足够的复合物稳定性，从而允许随后形成信号传导能力复合物。然后可以招募另一个相同亚型的受体，以及最多两个其他亚型的受体。因此，产生的受体排列主要由四种不同的受体组成，这与我们的相互作用分析一致，在一个亚型类中显示低配体受体特异性。对于BMP2，还可以发现仅含有一种I型受体链的异聚信号复合物，这进一步增加了复杂性。这表明，尽管配体受体混杂现象突出，但在这个受体有限的系统中可能会产生多种不同的信号。
Transforming growth factor (TGF)β superfamily members transduce signals by oligomerizing two classes of serine/threonine kinase receptors, termed type I and type II. In contrast to the large number of ligands only seven type I and five type II receptors have been identified in mammals, implicating a prominent promiscuity in ligand-receptor interaction. Since a given ligand can usually interact with more than one receptor of either subtype, differences in binding affinities and specificities are likely important for the generation of distinct ligand-receptor complexes with different signaling properties. In vitro interaction analyses showed two different prototypes of binding kinetics, 'slow on/slow off' and 'fast on/fast off'. Surprisingly, the binding specificity of ligands to the receptors of one subtype is only moderate. As suggested from the dimeric nature of the ligands, binding to immobilized receptors shows avidity due to cooperative binding caused by bivalent ligand-receptor interactions. To compare these in vitro observations to the situation in vivo, binding studies on whole cells employing homodimeric as well as heterodimeric bone morphogenetic protein 2 (BMP2) mutants were performed. Interestingly, low and high affinity binding sites were identified, as defined by the presence of either one or two BMP receptor (BMPR)-IA receptor chains, respectively. Both sites contribute to different cellular responses in that the high affinity sites allow a rapid transient response at low ligand concentrations whereas the low affinity sites facilitate sustained signaling but higher ligand concentrations are required. Binding of a ligand to a single high affinity receptor chain functioning as anchoring molecule and providing sufficient complex stability allows the subsequent formation of signaling competent complexes. Another receptor of the same subtype, and up to two receptors of the other subtype, can then be recruited. Thus, the resulting receptor arrangement can principally consist of four different receptors, which is consistent with our interaction analysis showing low ligand-receptor specificity within one subtype class. For BMP2, further complexity is added by the fact that heterooligomeric signaling complexes containing only one type I receptor chain can also be found. This indicates that despite prominent ligand receptor promiscuity a manifold of diverse signals might be generated in this receptor limited system.
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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：
11.4
作者：
Kotzsch, Alexander;Nickel, Joachim;Mueller, Thomas D.
通讯作者：
Mueller, Thomas D.
影响因子：
5.3
作者：
Hartung, Anke;Bitton-Worms, Keren;Knaus, Petra
通讯作者：
Knaus, Petra
影响因子：
2.9
作者：
Klages, Jochen;Kotzsch, Alexander;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
16
作者：
Greenwald, J;Groppe, J;Choe, S
通讯作者：
Choe, S