The insulin-like growth factor-binding protein (IGFBP) superfamily.
The insulin-like growth factor-binding protein (IGFBP) superfamily.
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DOI：
10.1210/edrv.20.6.0382
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发表时间：
1999-12
影响因子：
20.3
通讯作者：
V. Hwa;Y. Oh;Ron G. Rosenfeld
中科院分区：
文献类型：
--
作者：
V. Hwa;Y. Oh;Ron G. Rosenfeld
在过去的十年中，IGFBP家族的概念已经被广泛接受，基于结构相似性和以高亲和力结合IGFs的功能能力。是否存在其他潜在的IGFBPs尚不清楚。蛋白质的N端结构域与IGFBPs的N端具有惊人的结构相似性，并且对IGF的亲和力降低，但可证明，这一发现提出了这些蛋白质是否是“新的”IGFBPs的问题（22，23，217）。N-末端结构域与IGFBPs独特相关，长期以来被认为是IGF结合的关键。迄今为止，尚未确认此域的其他功能。因此，在其他蛋白质的N末端存在这种重要的IGFBP结构域必须被认为是重要的。尽管这些其他蛋白质似乎能够结合IGF，但它们相对较低的亲和力以及它们的主要生物学作用可能不直接涉及IGF肽的事实表明，它们可能不应被归类为暂时提出的IGFBP家族（22，23）。在所有IGFBP-rPs中，这个对六个IGFBPs高亲和力结合IGF如此关键的单一结构域的保守性也说明了其生物学重要性。从历史上看，也许在功能上，这导致了“IGFBP超家族”的命名。IGFBP超家族的分类和命名当然是任意的;最终相关的是潜在的生物学，其中大部分仍然有待破译。IGFBP相关蛋白的命名法来自IGFBP领域研究人员的共识（52）。显然，涉及每个IGFBP-rP工作的所有小组的命名法尚未达成更普遍的共识。进一步了解每种蛋白质的生物学功能有助于解决命名难题。目前，重新命名这些蛋白质IGFBP-rPs简化了与每个IGFBP相关蛋白质相关的多个名称，并加强了与IGFBPs关系的概念。在N-末端结构域之外，IGFBP-rPs和IGFBPs之间缺乏结构相似性。C-末端结构域确实与许多其他蛋白质中发现的其他内部结构域有相似之处。例如，IGFBPs C端与甲状腺球蛋白I型结构域的相似性表明IGFBPs在结构上也与携带相同结构域的许多其他蛋白质相关（87）。有趣的是，IGFBP超家族成员中不同C-末端结构域的功能包括与细胞表面或ECM的相互作用，这表明即使它们具有很少的序列相似性，C-末端结构域也可能在功能上相关。N-末端结构域的进化保守性和功能研究支持IGFBPs和IGFBP-rPs一起形成IGFBP超家族的概念。一个超家族划分了密切相关的（被归类为一个家族）和远亲的蛋白质。IGFBP超家族因此由远亲家族组成。IGFBP超家族的组成部分的模块化性质，特别是他们的高度保守的N-末端结构域的保存，似乎最好的解释的过程中的祖先基因编码这个域的外显子改组。在进化过程中，一些成员进化成高亲和力IGF结合剂，而另一些成员进化成低亲和力IGF结合剂，从而赋予IGFBP超家族通过IGF依赖性和IGF非依赖性手段影响细胞生长的能力（图10）。最后，史蒂芬·杰伊·古尔德（Stephen Jay Gould，218）说：“但是，在一个客观地划分为明显类别的世界中，分类并不是被动的排序手段。分类学是人类强加于自然的决定--关于自然秩序原因的理论。分类的历史变化编年史为我们提供了对概念革命的最佳洞察
Over the last decade, the concept of an IGFBP family has been well accepted, based on structural similarities and on functional abilities to bind IGFs with high affinities. The existence of other potential IGFBPs was left open. The discovery of proteins with N-terminal domains bearing striking structural similarities to the N terminus of the IGFBPs, and with reduced, but demonstrable, affinity for IGFs, raised the question of whether these proteins were "new" IGFBPs (22, 23, 217). The N-terminal domain had been uniquely associated with the IGFBPs and has long been considered to be critical for IGF binding. No other function has been confirmed for this domain to date. Thus, the presence of this important IGFBP domain in the N terminus of other proteins must be considered significant. Although these other proteins appear capable of binding IGF, their relatively low affinity and the fact that their major biological actions are likely to not directly involve the IGF peptides suggest that they probably should not be classified within the IGFBP family as provisionally proposed (22, 23). The conservation of this single domain, so critical to high-affinity binding of IGF by the six IGFBPs, in all of the IGFBP-rPs, as well, speaks to its biological importance. Historically, and perhaps, functionally, this has led to the designation of an "IGFBP superfamily". The classification and nomenclature for the IGFBP superfamily, are, of course, arbitrary; what is ultimately relevant is the underlying biology, much of which still remains to be deciphered. The nomenclature for the IGFBP related proteins was derived from a consensus of researchers working in the IGFBP field (52). Obviously, a more general consensus on nomenclature, involving all groups working on each IGFBP-rP, has yet to be reached. Further understanding of the biological functions of each protein should help resolve the nomenclature dilemma. For the present, redesignating these proteins IGFBP-rPs simplifies the multiple names already associated with each IGFBP related protein, and reinforces the concept of a relationship with the IGFBPs. Beyond the N-terminal domain, there is a lack of structural similarity between the IGFBP-rPs and IGFBPs. The C-terminal domains do share similarities to other internal domains found in numerous other proteins. For example, the similarity of the IGFBP C terminus to the thyroglobulin type-I domain shows that the IGFBPs are also structurally related to numerous other proteins carrying the same domain (87). Interestingly, the functions of the different C-terminal domains in members of the IGFBP superfamily include interactions with the cell surface or ECM, suggesting that, even if they share little sequence similarities, the C-terminal domains may be functionally related. The evolutionary conservation of the N-terminal domain and functional studies support the notion that IGFBPs and IGFBP-rPs together form an IGFBP superfamily. A superfamily delineates between closely related (classified as a family) and distantly related proteins. The IGFBP superfamily is therefore composed of distantly related families. The modular nature of the constituents of the IGFBP superfamily, particularly their preservation of an highly conserved N-terminal domain, seems best explained by the process of exon shuffling of an ancestral gene encoding this domain. Over the course of evolution, some members evolved into high-affinity IGF binders and others into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means (Fig. 10). A final word, from Stephen Jay Gould (218): "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon nature--theories about the causes of nature's order. The chronicle of historical changes in classification provides our finest insight into conceptual revolutions