The kexin-like proprotein convertases perform the initial proteolytic cleavages that ultimately generate a variety of different mature peptide and proteins, ranging from brain neuropeptides to endocrine peptide hormones, to structural proteins, among others. In this review, we present a general introduction to proprotein convertase structure and biochemistry, followed by a comprehensive discussion of each member of the kexin-like subfamily of proprotein convertases. We summarize current knowledge of human proprotein convertase insufficiency syndromes, including genome-wide analyses of convertase polymorphisms, and compare these to convertase null and mutant mouse models. These mouse models have illuminated our understanding of the roles specific convertases play in human disease and have led to the identification of convertase-specific substrates; for example, the identification of procorin as a specific PACE4 substrate in the heart. We also discuss the limitations of mouse null models in interpreting human disease, such as differential precursor cleavage due to species-specific sequence differences, and the challenges presented by functional redundancy among convertases in attempting to assign specific cleavages and/or physiological roles. However, in most cases, knockout mouse models have added substantively both to our knowledge of diseases caused by human proprotein convertase insufficiency and to our appreciation of their normal physiological roles, as clearly seen in the case of the furin, proprotein convertase 1/3, and proprotein convertase 5/6 mouse models. The creation of more sophisticated mouse models with tissue- or temporally-restricted expression of specific convertases will improve our understanding of human proprotein convertase insufficiency and potentially provide support for the emerging concept of therapeutic inhibition of convertases.

中文翻译：

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人类前蛋白转化酶不足的小鼠模型

kexin 样前蛋白转化酶进行最初的蛋白水解切割，最终产生各种不同的成熟肽和蛋白质，从脑神经肽到内分泌肽激素，再到结构蛋白等。在这篇综述中，我们对前蛋白转化酶的结构和生物化学进行了一般性介绍，然后对前蛋白转化酶的 kexin 样亚家族的每个成员进行了全面讨论。我们总结了人类前蛋白转化酶不足综合征的当前知识，包括转化酶多态性的全基因组分析，并将这些与转化酶无效和突变小鼠模型进行比较。这些小鼠模型阐明了我们对特定转化酶在人类疾病中的作用的理解，并导致了转化酶特异性底物的鉴定；例如，将 procorin 鉴定为心脏中特定的 PACE4 底物。我们还讨论了小鼠无效模型在解释人类疾病方面的局限性，例如由于物种特异性序列差异导致的差异前体切割，以及在试图分配特定切割和/或生理作用时转化酶之间的功能冗余所带来的挑战。然而，在大多数情况下，敲除小鼠模型极大地增加了我们对人类前蛋白转化酶不足引起的疾病的认识，以及我们对其正常生理作用的认识，这在弗林蛋白酶前蛋白转化酶 1/3 的情况下可以清楚地看到，和前蛋白转化酶 5/6 小鼠模型。