Van de Ven W J, Roebroek A J, Van Duijnhoven H L
Laboratory for Molecular Oncology, University of Leuven, Belgium.
Crit Rev Oncog. 1993;4(2):115-36.
Production of a broad spectrum of regulatory proteins in eukaryotes occurs via an intricate cascade of biosynthetic and secretory processes. Often these proteins initially are synthesized as parts of higher molecular weight, but inactive, precursor proteins. Specific endoproteolytic processing of these proproteins is required to generate the regulatory proteins in a mature and biologically active form. Such endoproteolysis generally occurs at cleavage sites consisting of particular sequence motifs of basic amino acids, often paired basic residues. This phenomenon, first observed almost 25 years ago, has intrigued scientists ever since then. Nevertheless, the responsible enzymes remained elusive for long. The first known eukaryotic enzyme with the exquisite cleavage specificity for paired basic amino acid residues was the prohormone processing enzyme kexin (EC 3.4.21.61), a subtilisin-like serine protease that is encoded by the KEX2 gene of yeast Saccharomyces cerevisiae. Recently, a number of kexin-like mammalian proprotein-processing enzymes were discovered. The enzyme furin, which is encoded by the fur gene, was the first and can be considered the prototype of a mammalian subclass of subtilisin-like serine proteases. It is predicted to contain a "prepro" domain, a subtilisin-like catalytic domain, a middle domain, a cysteine-rich region, a transmembrane anchor, and a cytoplasmic domain. Furin is expressed in a wide variety of tissues, perhaps even in all tissues. In all likelihood, it is the enzyme responsible for the proteolytic bioactivation of a wide variety of precursor proteins. Two other novel mammalian proprotein-processing enzymes are PC1 (also known as PC3) and PC2. Some of the protein domains of these enzymes resemble those in kexin and furin, however, there are also differences. The PC1/PC3 and PC2 enzymes exhibit a more restricted expression pattern than furin. It has been suggested that PC1/PC3 and PC2 are involved primarily in the processing of prohormones within the regulated secretory pathway of cells of endocrine and neural tissue. Recently, the coding sequences for two other candidate mammalian proprotein-processing enzymes were identified. They were called PACE4 and PC4. Like that of furin, the tissue distribution of PACE4 is widespread. PC4, however, may represent a candidate for a precursor-processing endoprotease that is specifically expressed in the testicular germ cells. Finally, DNA sequences encoding kexin- and furin-like candidate pro-protein-processing enzymes have been identified in Drosophila melanogaster, Dfur1 and Dfur2 genes; in Xenopus laevis, Xen-14 gene; and in Caenorhabditis elegans, bli-4 gene.(ABSTRACT TRUNCATED AT 400 WORDS)
真核生物中多种调节蛋白的产生是通过一系列复杂的生物合成和分泌过程实现的。这些蛋白通常最初是以较高分子量但无活性的前体蛋白形式合成的。需要对这些前体蛋白进行特定的内切蛋白水解加工，才能产生成熟且具有生物活性形式的调节蛋白。这种内切蛋白水解作用一般发生在由特定碱性氨基酸序列基序组成的切割位点，通常是成对的碱性残基。这一现象在近25年前首次被观察到，从那时起就一直吸引着科学家们。然而，负责的酶长期以来一直难以捉摸。第一个已知的对成对碱性氨基酸残基具有精确切割特异性的真核酶是激素原加工酶克新（EC 3.4.21.61），它是一种枯草杆菌蛋白酶样丝氨酸蛋白酶，由酿酒酵母的KEX2基因编码。最近，发现了一些类似克新的哺乳动物前体蛋白加工酶。由fur基因编码的弗林蛋白酶是第一个，可被视为枯草杆菌蛋白酶样丝氨酸蛋白酶哺乳动物亚类的原型。预计它含有一个“前原”结构域、一个枯草杆菌蛋白酶样催化结构域、一个中间结构域、一个富含半胱氨酸的区域、一个跨膜锚定结构和一个细胞质结构域。弗林蛋白酶在多种组织中表达，甚至可能在所有组织中都有表达。很可能它就是负责多种前体蛋白蛋白水解生物激活的酶。另外两种新型的哺乳动物前体蛋白加工酶是PC1（也称为PC3）和PC2。这些酶的一些蛋白结构域与克新和弗林蛋白酶中的结构域相似，然而，也存在差异。PC1/PC3和PC2酶的表达模式比弗林蛋白酶更受限。有人提出，PC1/PC3和PC2主要参与内分泌和神经组织细胞的调节分泌途径中激素原的加工。最近，又鉴定出另外两种候选的哺乳动物前体蛋白加工酶的编码序列。它们被称为PACE4和PC4。与弗林蛋白酶一样，PACE4的组织分布很广泛。然而，PC4可能是一种在前睾丸生殖细胞中特异性表达的前体加工内切蛋白酶的候选者。最后，在黑腹果蝇中鉴定出了编码类似克新和弗林蛋白酶的候选前体蛋白加工酶的DNA序列，即Dfur1和Dfur2基因；在非洲爪蟾中，是Xen-14基因；在秀丽隐杆线虫中，是bli-4基因。（摘要截短至400字）
