Structure and function of the anaphylatoxins.
Structure and function of the anaphylatoxins.
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DOI：
10.1007/978-3-642-82416-6_5
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发表时间：
1984
期刊：
影响因子：
--
通讯作者：
T. Hugli
中科院分区：
文献类型：
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作者：
T. Hugli
过敏毒素分子的化学和物理特性提供了这些生物活性蛋白质的结构的合理清晰的描述。来自人类和许多动物物种的C3 a、C4 a和C5 a的一级结构已被阐明，显然这三种过敏毒素在遗传上是相关的。过敏毒素蛋白质链的长度为74至78个残基，当比较种内或种间的C3 a、C4 a和C5 a时，不少于30%的残基是同源的。合成肽的研究有助于识别过敏毒素功能所必需的分子特征。从过敏毒素的合成类似物肽的结构-功能研究中获得的信息定义了这些效应分子中的推定“活性位点”。在C3 a和C4 a的羧基末端的线性序列满足“活性位点”的所有标准，因为相同序列的合成肽可以模拟天然因子的生物学作用。在人类C3 a的情况下，已经进行了晶体学分析，并在3.2 μ m水平上阐明了三维结构。C3 a的晶体结构提供了关于α螺旋区域的有价值的新信息，并确定了链内二硫键的排列。两者合计，现在积累的过敏毒素的结构数据允许这些蛋白质的分子建模，指定有利于天然结构的构象排列，并具体定位的效应位点。此外，元素的基本活性位点已被定义与精确的模型，提出详细说明的确切性质的过敏毒素和特定的细胞receptors. Biological表征的过敏毒素之间的配体相互作用继续在快速的步伐，每一个进步提供了一个更清晰的视图，这些体液介质在宿主防御的作用。已知对过敏毒素的多种反应发生在细胞水平，并以类过敏方式介导。这些因子在组织水平上作用的多样性很容易用过敏毒素刺激的多种细胞类型来解释。对过敏毒素的细胞反应可能是最容易定义和研究的;然而，组织和全身效应更准确地反映了过敏毒素的生理作用。在了解过敏毒素介导两种主要组织效应（即增强血管通透性和诱导平滑肌收缩）的机制方面已取得相当大的进展。来自花生四烯酸的生物活性脂质的主要作用已被确定为这些反应的主要成分。此外，在阐明不道德介质和细胞介质之间在引发组织对过敏毒素反应方面的关系方面也正在取得进展。随着这些机制的阐明，这些体液介质在病理生理条件下的全身效应和参与的意义将最终被理解。
Chemical and physical characterization of the anaphylatoxin molecules have provided a reasonably clear description of the architecture of these bioactive proteins. The primary structures of C3a, C4a, and C5a from man and from a number of animal species have been elucidated, and it is apparent that the three anaphylatoxins are genetically related. The anaphylatoxin protein chains very in length from 74 to 78 residues and no fewer than 30% of the residues are homologous when comparing C3a, C4a, and C5a within or between species. Synthetic peptide studies have been instrumental in identifying molecular features essential for the function of anaphylatoxins. Information gleened from the structure-function studies with synthetic analogue peptides of the anaphylatoxins define putative “active sites” in these effector molecules. Linear sequences at the carboxy-terminus of C3a and C4a fulfill all of the criteria of an “active site,“ in that synthetic peptides of an identical sequence can mimic the biologic actions of the natural factors. In the case of human C3a, a crystallographic analysis has been performed and a three dimensional structure was elucidated at the 3.2 Å level. The crystalline structure of C3a provides valuable new information regarding the alpha helical regions and identifies the arrangement of intra-chain disulfide linkages. Taken together, the structural data now accumulated for anaphylatoxins permit molecular modelling of these proteins, designates favored conformational arrangements of the native structures, and specifically localizes the effector sites. Furthermore, elements at the essential active site have been defined with such precision that models are proposed detailing the exact nature of ligand interactions between anaphylatoxins and specific cellular receptors.Biologic characterization of the anaphylatoxins continues at a rapid pace and each advance provides a clearer view of the role of these humoral mediators in host defense. A variety of responses to anaphylatoxins are known to occur at the cellular level and are mediated in a hormone-like fashion. Diversity of action for these factors at the tissue level is readily explained by the numerous cell types stimulated by the anaphylatoxins. Cellular responses to the anaphylatoxins are perhaps the most easily defined and studied; however, tissue and systemic effects more accurately reflect the physiologic role of anaphylatoxins. Considerable progress has been made in understanding the mechanisms whereby anaphylatoxins mediate two major tissue effects, namely enhancement of vascular permeability and induction of smooth muscle contraction. A predominant role for bioactive lipids derived from arachidonate has been identified as a major component of these responses. Also, progress is being made in elucidating relationships between Immoral and cellular mediators in eliciting tissue responses to the anaphylatoxins. As these mechanisms are clarified, the significance of systemic effects and involvement of these humoral mediators in pathophysiologic conditions will ultimately be understood.