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首页> 外文期刊>The FEBS journal >Hepatocyte growth factor activator (HGFA): molecular structure and interactions with HGFA inhibitor-1 (HAI-1)
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Hepatocyte growth factor activator (HGFA): molecular structure and interactions with HGFA inhibitor-1 (HAI-1)

机译：肝细胞生长因子激活剂（HGFA）：分子结构及其与HGFA抑制剂1（HAI-1）的相互作用

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摘要

The trypsin-like serine protease hepatocyte growth factor activator (HGFA) undergoes proteolytic activation during blood coagulation, resulting in a 34 kDa 'short form', consisting mainly of the protease domain. The crystal structures of the recombinantly expressed HGFA 'short form' discussed herein have provided molecular insights into its interaction with inhibitors and substrates, as well as the regulation of catalytic activity. The HGFA structures revealed enzymatically competent and noncompetent forms associated with the conformational states of two substrate specificity-determining loops, the 220-loop and 99-loop. The implied dynamic behavior of these loops, which are intimately involved in substrate interaction, has precedents in other members of the S1 family of serine proteases, and may be associated with specific mechanisms of enzyme regulation. Furthermore, HGFA activity is strongly inhibited by HGFA inhibitor-1, a membrane-spanning multidomain inhibitor containing two Kunitz domains, of which only the N-terminal Kunitz domain-1 (KD1) inhibits enzymatic activity. In the structure of the KD1-HGFA complex, the inhibitor interacts with the active site region by making contacts with all substrate specificity-determining loops and by occupying subsites S1, S2 and S4 in a substrate-like manner. In fact, the side chains of KD1 residues occupying these sites are virtually superimposable on the P1, P2 and P4 residues of the pro-hepatocyte growth factor-derived substrate mimic Lys-Gln-Leu-Arg chloromethyl ketone bound to HGFA. These structures also allow us to rationalize the apparently narrow substrate specificity of HGFA, which is limited to the two known macromolecular substrates pro-hepatocyte growth factor and pro-macrophage-stimulating protein.
机译：胰蛋白酶样丝氨酸蛋白酶肝细胞生长因子激活剂（HGFA）在血液凝结过程中发生蛋白水解激活，产生34 kDa的“短形式”，主要由蛋白酶结构域组成。本文讨论的重组表达的HGFA“短形式”的晶体结构为分子与抑制剂和底物的相互作用以及催化活性的调节提供了分子见解。 HGFA结构揭示了与两个底物特异性确定环（220环和99环）的构象状态相关的酶促和非能力形式。这些环的隐含动态行为与底物相互作用密切相关，在丝氨酸蛋白酶S1家族的其他成员中具有先例，并且可能与酶调节的特定机制有关。此外，HGFA抑制剂-1强烈抑制了HGFA的活性，HGFA抑制剂-1是一种跨膜的多域抑制剂，包含两个Kunitz域，其中只有N端Kunitz域1（KD1）抑制酶活性。在KD1-HGFA复合物的结构中，抑制剂通过与所有底物特异性决定环接触并通过以底物样方式占据亚位点S1，S2和S4与活性位点区域相互作用。实际上，占据这些位点的KD1残基的侧链实际上可以重叠在原肝细胞生长因子衍生的底物模拟HGFA的Lys-Gln-Leu-Arg氯甲基酮的P1，P2和P4残基上。这些结构还使我们能够合理化HGFA的明显窄的底物特异性，该特异性仅限于两种已知的大分子底物前肝细胞生长因子和前巨噬细胞刺激蛋白。

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