Proprotein and prohormone convertases:: a family of subtilases generating diverse bioactive polypeptides
Proprotein and prohormone convertases:: a family of subtilases generating diverse bioactive polypeptides
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DOI：
10.1016/s0006-8993(99)01909-5
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发表时间：
1999-11-27
期刊：
影响因子：
2.9
通讯作者：
Chrétien, M
中科院分区：
文献类型：
--
作者：
Seidah, NG;Chrétien, M
原蛋白和原激素是生物活性蛋白和多肽以及神经肽的基本单位，在分泌途径中通过有限的蛋白质水解产生。前体通常在一般基序(K/R)-(X)(n)-(K/R)向下箭头处断裂，其中n = 0,2,4或6，X是任何氨基酸，通常不是Cys。目前已鉴定出七种哺乳动物前体转化酶：PC1、PC2、furin、PC4、PC5、PACE4和PC7。这些酶中的每一种，单独或与其他酶结合，都负责大脑和外周细胞中多种多肽前体的组织特异性加工。这种组合机制以精细调节的方式产生大量生物活性分子。零小鼠的生产允许评估转化酶在体内的关键作用。因此，雄性PC4（-/-）小鼠是不育的，furin（-/-）和PC1（-/-）小鼠是胚胎致死的，PC2（-/-）小鼠是轻度糖尿病和矮胖的。有趣的是，缺乏7B2（一种pc2特异性结合蛋白）的动物表现出库欣样综合征，并在出生后不久死亡。最近，发现了一类新的枯草菌素-激酶样转化酶的第一个成员，称为SKI-1。它的结构更接近于裂解素，而不是哺乳动物的pc。从它加工甾醇调节元件结合蛋白和前脑源性神经营养因子的能力推断，它在基序(R/K)- x - x -（L，T）向下箭头处具有特异性裂解。因此，虽然pc负责神经肽、粘附分子、受体、生长因子、细胞表面糖蛋白和酶的加工，但SKI-1切割对控制胆固醇和脂肪酸代谢以及神经元保护和生长至关重要的原蛋白。(C) 1999 Elsevier Science B.V.版权所有
Proproteins and prohormones are the fundamental units from which bioactive proteins and peptides as well as neuropeptides are derived by limited proteolysis within the secretory pathway. Precursors are usually cleaved at the general motif (K/R)-(X)(n)-(K/R)down arrow, where n = 0, 2, 4 or 6 and X is any amino acid and usually is not a Cys. Seven mammalian precursor convertases (PCs) have been identified: PC1, PC2, furin, PC4, PC5, PACE4 and PC7. Each of these enzymes, either alone or in combination with others, is responsible for the tissue-specific processing of multiple polypeptide precursors both in the brain and in periphery. This combinatorial mechanism generates a large diversity of bioactive molecules in an exquisitively regulated manner. The production of null mice allowed the assessment of the critical role of convertases in vivo. Thus, male PC4 (-/-) mice are infertile, furin (-/-) and PC1(-/-) mice are embryonic lethal, and PC2(-/-)mice are mildly diabetic and runted. Interestingly, animals deficient in 7B2, a PC2-specific binding protein, exhibit a Cushing-like syndrome and die soon after birth. Recently, the first member of a new class of subtilisin-kexin-like convertases, called SKI-1, was identified. Its structure is closer to pyrolysin than to mammalian PCs and it exhibits a specificity for cleavage at the motif (R/K)-X-X-(L,T)down arrow as deduced from its ability to process sterol regulatory element binding proteins and pro-brain derived neurotrophic factor. Thus, while PCs are responsible for the processing of neuropeptides, adhesion molecules, receptors, growth factors, cell surface glycoprotein and enzymes, SKI-1 cleaves proproteins that are critical for the control of cholesterol and fatty acid metabolism and for neuronal protection and growth. (C) 1999 Elsevier Science B.V. All rights reserved.