Donate L E, Gherardi E, Srinivasan N, Sowdhamini R, Aparicio S, Blundell T L
Department of Crystallography, Birkbeck College, University of London, United Kingdom.
Protein Sci. 1994 Dec;3(12):2378-94. doi: 10.1002/pro.5560031222.
Plasminogen-related growth factors, a new family of polypeptide growth factors with the basic domain organization and mechanism of activation of the blood proteinase plasminogen, include hepatocyte growth factor/scatter factor (HGF/SF), a potent effector of the growth, movement, and differentiation of epithelia and endothelia, and hepatocyte growth factor-like/macrophage stimulating protein (HGF1/MSP), an effector of macrophage chemotaxis and phagocytosis. Phylogeny of the serine proteinase domains and analysis of intron-exon boundaries and kringle sequences indicate that HGF/SF, HGF1/MSP, plasminogen, and apolipoprotein (a) have evolved from a common ancestral gene that consisted of an N-terminal domain corresponding to plasminogen activation peptide (PAP), 3 copies of the kringle domain, and a serine proteinase domain. Models of the N domains of HGF/SF, HGF1/MSP, and plasminogen, characterized by the presence of 4 conserved Cys residues forming a loop in a loop, have been modeled based on disulfide-bond constraints. There is a distinct pattern of charged and hydrophobic residues in the helix-strand-helix motif proposed for the PAP domain of HGF/SF; these may be important for receptor interaction. Three-dimensional structures of the 4 kringle and the serine proteinase domains of HGF/SF were constructed by comparative modeling using the suite of programs COMPOSER and were energy minimized. Docking of a lysine analogue indicates a putative lysine-binding pocket within kringle 2 (and possibly another in kringle 4). The models suggest a mechanism for the formation of a noncovalent HGF/SF homodimer that may be responsible for the activation of the Met receptor. These data provide evidence for the divergent evolution and structural similarity of plasminogen, HGF/SF, and HGF1/MSP, and highlight a new strategy for growth factor evolution, namely the adaptation of a proteolytic enzyme to a role in receptor activation.
纤溶酶原相关生长因子是一类新的多肽生长因子家族，其具有与血液蛋白酶纤溶酶原相同的基本结构域组织和激活机制，包括肝细胞生长因子/散射因子（HGF/SF），它是上皮细胞和内皮细胞生长、运动及分化的强效效应因子，以及肝细胞生长因子样/巨噬细胞刺激蛋白（HGF1/MSP），它是巨噬细胞趋化性和吞噬作用的效应因子。丝氨酸蛋白酶结构域的系统发育以及内含子-外显子边界和kringle序列分析表明，HGF/SF、HGF1/MSP、纤溶酶原和载脂蛋白(a)是由一个共同的祖先基因进化而来，该祖先基因由一个对应于纤溶酶原激活肽（PAP）的N端结构域、3个kringle结构域拷贝和一个丝氨酸蛋白酶结构域组成。基于二硫键限制，已对HGF/SF、HGF1/MSP和纤溶酶原的N结构域模型进行了建模，其特征是存在4个保守的半胱氨酸残基形成一个环中环。在为HGF/SF的PAP结构域提出的螺旋-链-螺旋基序中存在独特的带电和疏水残基模式；这些可能对受体相互作用很重要。使用COMPOSER程序套件通过比较建模构建了HGF/SF的4个kringle和丝氨酸蛋白酶结构域的三维结构，并进行了能量最小化。赖氨酸类似物的对接表明在kringle 2内有一个假定的赖氨酸结合口袋（kringle 4中可能还有另一个）。这些模型提出了一种非共价HGF/SF同二聚体形成的机制，这可能负责Met受体的激活。这些数据为纤溶酶原、HGF/SF和HGF1/MSP的趋异进化和结构相似性提供了证据，并突出了生长因子进化的一种新策略，即将一种蛋白水解酶适应于受体激活的作用。
