α2-Macroglobulins: Structure and Function
α2-Macroglobulins: Structure and Function
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DOI：
10.1007/978-3-319-46503-6_6
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发表时间：
2017-01-01
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影响因子：
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通讯作者：
Goulas, Theodoros
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文献类型：
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作者：
Garcia-Ferrer, Irene;Marrero, Aniebrys;Goulas, Theodoros
α(2)-巨球蛋白是广谱内肽酶抑制剂，到目前为止，它的特征来自后生动物(脊椎动物和无脊椎动物)和革兰氏阴性细菌。它们的结构和生化特性揭示了两种相关的作用模式：“金星捕蝇器”和“捕蝇器”机制。在这两种情况下，肽酶在切割高度灵活的诱饵区域后，会引发α(2)-巨球蛋白的大规模构象重排，从而导致它们被困住。在一些同系物中，第二个作用发生，涉及一个高活性的β-半胱氨基-伽马-谷氨酰硫酯键，它与裂解的多肽酶共价结合，从而有助于酶：抑制物复合体的进一步稳定。捕获的多肽酶仍然具有活性，但由于空间位阻，限制了对其底物的访问。通过这种方式，人的α(2)-巨球蛋白同系物调节复杂的生物过程中的蛋白质分解，如营养、信号和组织重构，但也在感染和毒化过程中保护宿主机体免受外部毒素和其他毒力因子的攻击。同时，它通过调节细胞因子的活性，调节激素、生长因子、脂质因子等蛋白质的活性，参与其他多种生物学功能的发挥，对生理产生重大影响。同样，细菌α(2)-巨球蛋白可能通过保护细胞壁成分免受多肽酶的攻击而参与防御，或通过识别宿主多肽酶和/或抗菌肽参与宿主-病原体的相互作用。α(2)-巨球蛋白在真核生物和原核生物中的分布比最初认为的更广泛，并发挥着多功能的作用，因此，对其进行研究是必要的。
alpha(2)-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the "Venus flytrap"and the "snap-trap"mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of alpha(2)-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment. In some homologs, a second action takes place that involves a highly reactive beta-cysteinyl-gamma-glutamyl thioester bond, which covalently binds cleaving peptidases and thus contributes to the further stabilization of the enzyme: inhibitor complex. Trapped peptidases are still active, but have restricted access to their substrates due to steric hindrance. In this way, the human alpha(2)-macroglobulin homolog regulates proteolysis in complex biological processes, such as nutrition, signalling, and tissue remodelling, but also defends the host organism against attacks by external toxins and other virulence factors during infection and envenomation. In parallel, it participates in several other biological functions by modifying the activity ofcytokines and regulating hormones, growth factors, lipid factors and other proteins, which has a great impact on physiology. Likewise, bacterial alpha(2)-macroglobulins may participate in defence by protecting cell wall components from attacking peptidases, or in host-pathogen interactions through recognition of host peptidases and/or antimicrobial peptides. alpha(2)-macroglobulins are more widespread than initially thought and exert multifunctional roles in both eukaryotes and prokaryotes, therefore, their on-going study is essential.