Rozwarski D A, Gronenborn A M, Clore G M, Bazan J F, Bohm A, Wlodawer A, Hatada M, Karplus P A
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853.
Structure. 1994 Mar 15;2(3):159-73. doi: 10.1016/s0969-2126(00)00018-6.
Cytokines and growth factors are soluble proteins that regulate the development and activities of many cell types. One group of these proteins have structures based on a four-helix bundle, though this similarity is not apparent from amino acid sequence comparisons. An understanding of how diverse sequences can adopt the same fold would be useful for recognizing and aligning distant homologs and for applying structural information gained from one protein to other sequences.
We have approached this problem by comparing the five known structures which adopt a granulocyte-macrophage colony-stimulating factor (GM-CSF)-like, or short-chain fold: interleukin (IL)-4, GM-CSF, IL-2, IL-5, and macrophage colony-stimulating factor. The comparison reveals a common structural framework of five segments including 31 inner-core and 30 largely exposed residues. Buried polar interactions found in each protein illustrate how complementary substitutions maintain protein stability and may help specify unique core packing. A profile based on the known structures is not sufficient to guarantee accurate amino acid sequence alignments with other family members. Comparisons of the conserved short-chain framework with growth hormone define the optimal structural alignment.
Our results are useful for extrapolating functional results among the short-chain cytokines and growth hormone, and provide a foundation for similar characterization of other subfamilies. These results also show that the placement of polar residues at different buried positions in each protein complicates sequence comparisons, and they document a challenging test case for methods aimed at recognizing and aligning distant homologs.
细胞因子和生长因子是可调节多种细胞类型发育和活性的可溶性蛋白质。这类蛋白质中的一组具有基于四螺旋束的结构，尽管从氨基酸序列比较中这种相似性并不明显。了解不同序列如何采用相同的折叠方式，对于识别和比对远源同源物以及将从一种蛋白质获得的结构信息应用于其他序列将是有用的。
我们通过比较五种已知结构来解决这个问题，这五种结构采用粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）样或短链折叠：白细胞介素（IL）-4、GM - CSF、IL - 2、IL - 5和巨噬细胞集落刺激因子。比较揭示了由五个片段组成的共同结构框架，包括31个内核残基和30个大部分暴露的残基。在每种蛋白质中发现的埋藏极性相互作用说明了互补取代如何维持蛋白质稳定性，并可能有助于确定独特的核心堆积。基于已知结构的图谱不足以保证与其他家族成员进行准确的氨基酸序列比对。将保守的短链框架与生长激素进行比较确定了最佳的结构比对。
我们的结果对于推断短链细胞因子和生长激素之间的功能结果是有用的，并为其他亚家族的类似表征提供了基础。这些结果还表明，极性残基在每种蛋白质中不同埋藏位置的分布使序列比较变得复杂，并且它们为旨在识别和比对远源同源物的方法提供了一个具有挑战性的测试案例。
