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 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.

Keywords: PCSK; knockout mouse models; precursor processing; proprotein convertase.

Graphical abstract

Figure 1.

Proprotein convertase structure. This figure depicts the structures of the various basic residue-specific proprotein convertases (human). The membrane-spanning signal peptides and transmembrane domains (when present) are shown in blue. The comparatively large propeptides (purple) are cleaved after basic residues, often at 2 sites, the primary (light arrow) and secondary (dark arrow) cleavage site; the primary site is always an intermolecular cleavage. The catalytic domain (pink) is the most conserved domain for each enzyme; shown here are the catalytic residues D (Asp), H (His) and S (Ser), as well as the oxyanion hole residue N (Asn) (D = Asp only in PC2). The P or homoB domain (red) is thought to confer stability to the catalytic domain and is required for expression of active enzyme. The carboxy-terminal segments following the P domain are quite variable between convertases; certain enzymes contain a Cys-rich domain (yellow) which can interact with surface glycoproteins. Cytoplasmic tails (orange) present in furin, PC5B (PC5/6B) and PC7 have been shown to confer subcellular targeting information. All enzymes are N-glycosylated to a variable extent (shown with red circles). Of note, other posttranslational modifications not depicted here, including phosphorylation and palmitoylation, may also be present. Adapted from Seidah NG, Nat Rev Drug Discov. 2012 (1).