Mouse Models of Human Proprotein Convertase Insufficiency
| Autor: | Iris Lindberg, Manita Shakya |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
animal structures Endocrinology Diabetes and Metabolism Mutant Proprotein convertase 1 Review 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Human disease Animals Humans Furin Proprotein Convertase 5 biology fungi Proprotein convertase Cell biology Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Knockout mouse biology.protein Proprotein Convertases Genome-Wide Association Study |
| Zdroj: | Endocr Rev |
| ISSN: | 1945-7189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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