Mouse Models of Human Proprotein Convertase Insufficiency

Abstract

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 pro-corin 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, PC1/3, and PC5/6 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.

Ciliary Generation of a Peptidergic Sexual Signal

“…The pro-domains of subtilisin-like endoproteases facilitate catalytic domain folding and inhibit activity. Protease activation requires autoproteolytic cleavage, separating the pro-domain from the catalytic domain (Shakya and Lindberg, 2020). Additional cleavages within the pro-domain may also be required for pro-domain release and S8 domain activation.…”

“…7B). Activation of subtilisin-like prohormone convertases generally requires autoproteolytic cleavage and subsequent dissociation of the pro-domain (Shakya and Lindberg, 2020). Clustal analysis identified the -Gly-Arg-Arg site that immediately precedes the catalytic domain as the likely site for autoactivation.…”

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

“…PC1/3, encoded by the PCSK1 gene, is widely distributed within neuronal and endocrine cells throughout the body, where it contributes to the processing of a large number of physiologically important peptide precursors, including POMC, most hypothalamic neuropeptide precursors, and prohormones such as proinsulin (reviewed in Shakya and Lindberg) ( 58 ). Common PCSK1 polymorphisms are associated with obesity in a variety of different human populations ( 59 ).…”

“…While for obvious reasons brain αMSH has never been measured in patients with inactivating PCSK1 mutations, levels of a variety of different peptide precursors are elevated in patient blood ( 61-63 ). New cases of severe pediatric PCSK1 insufficiency are reported each year (reviewed in ( 58 , 59 ); see also ( 64 , 65 )).…”

“…These data support the idea that background strain differences play a huge role in phenotype determination in these 2 nulls, and likely also affect differential results obtained in other obesity-related mouse models. In humans, polymorphisms in PCSK2 are associated with alterations in glucose handling (reviewed in Shakya and Lindberg) ( 58 ); however, inactivating mutations in PCSK2 have not been reported.…”