Deciphering the Molecular and Functional Basis of Dbl Family Proteins A NOVEL SYSTEMATIC APPROACH TOWARD CLASSIFICATION OF SELECTIVE ACTIVATION OF THE Rho FAMILY PROTEINS
Deciphering the Molecular and Functional Basis of Dbl Family Proteins A NOVEL SYSTEMATIC APPROACH TOWARD CLASSIFICATION OF SELECTIVE ACTIVATION OF THE Rho FAMILY PROTEINS
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DOI：
10.1074/jbc.m112.429746
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发表时间：
2013-02-08
影响因子：
4.8
通讯作者：
Ahmadian, Mohammad Reza
中科院分区：
文献类型：
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作者：
Jaiswal, Mamta;Dvorsky, Radovan;Ahmadian, Mohammad Reza
鸟嘌呤核苷酸交换因子的弥漫性 B 细胞淋巴瘤 (Dbl) 家族是 Rho 家族蛋白的直接激活剂。 Rho 家族蛋白参与几乎所有细胞过程，从基本过程（例如细胞极性的建立）到高度专业化的过程（例如血管平滑肌细胞的收缩）。众所周知，Rho 蛋白的异常激活在癌症、传染性和认知障碍以及心血管疾病中发挥着至关重要的作用。然而，人类体内存在 74 种 Dbl 蛋白和 25 种 Rho 相关蛋白（这些蛋白在很大程度上尚未被表征），导致识别特定上游途径的复杂性不断增加。因此，我们全面研究了 Dbl 蛋白家族 21 种代表的序列-结构-功能-性质关系，了解它们对 12 种 Rho 家族蛋白的特异性和活性。荟萃分析方法为广泛分析 Dbl 家族蛋白的功能特性提供了前所未有的机会，包括催化效率、底物选择性和信号传导特异性。我们的分析为以下方面提供了新的见解：（i）了解各种 Rho 蛋白成员在核苷酸交换中的相对差异； (ii) 比较和定义一大组代表性 Dbl 蛋白对 12 个 Rho 蛋白的个体和总体鸟嘌呤核苷酸交换因子活性； (iii) 根据 Dbl 家族的催化效率和序列结构关系将其分为功能不同的类别； (iv) 鉴定保守氨基酸作为 Dbl 和 Rho 蛋白相互作用的指纹； (v)定义在Dbl亚家族内部而不是在Dbl亚家族之间保守的氨基酸序列。因此，此类特异性决定残基的特征鉴定了Dbl亚家族内保守的区域或簇。
The diffuse B-cell lymphoma (Dbl) family of the guanine nucleotide exchange factors is a direct activator of the Rho family proteins. The Rho family proteins are involved in almost every cellular process that ranges from fundamental (e.g. the establishment of cell polarity) to highly specialized processes (e. g. the contraction of vascular smooth muscle cells). Abnormal activation of the Rho proteins is known to play a crucial role in cancer, infectious and cognitive disorders, and cardiovascular diseases. However, the existence of 74 Dbl proteins and 25 Rho-related proteins in humans, which are largely uncharacterized, has led to increasing complexity in identifying specific upstream pathways. Thus, we comprehensively investigated sequence-structure-function-property relationships of 21 representatives of the Dbl protein family regarding their specificities and activities toward 12 Rho family proteins. The meta-analysis approach provides an unprecedented opportunity to broadly profile functional properties of Dbl family proteins, including catalytic efficiency, substrate selectivity, and signaling specificity. Our analysis has provided novel insights into the following: (i) understanding of the relative differences of various Rho protein members in nucleotide exchange; (ii) comparing and defining individual and overall guanine nucleotide exchange factor activities of a large representative set of the Dbl proteins toward 12 Rho proteins; (iii) grouping the Dbl family into functionally distinct categories based on both their catalytic efficiencies and their sequence-structural relationships; (iv) identifying conserved amino acids as fingerprints of the Dbl and Rho protein interaction; and (v) defining amino acid sequences conserved within, but not between, Dbl subfamilies. Therefore, the characteristics of such specificity-determining residues identified the regions or clusters conserved within the Dbl subfamilies.