Processing of peptide and hormone precursors at the dibasic cleavage sites

Abstract

Many functionally important cellular peptides and proteins, including hormones, neuropeptides, and growth factors, are synthesized as inactive precursor polypeptides, which require post-translational proteolytic processing to become biologically active polypeptides. This is achieved by the action of a relatively small number of proteases that belong to a family of seven subtilisin-like proprotein convertases (PCs) including furin. In view of this, this review focuses on the importance of privileged secondary structures and of given amino acid residues around basic cleavage sites in substrate recognition by these endoproteases. In addition to their participation in normal cell functions, PCs are crucial for the initiation and progress of many important diseases. Hence, these proteases constitute potential drug targets in medicine. Accordingly, this review also discusses the approaches used to shed light on the cleavage preference and the substrate specificity of the PCs, a prerequisite to select which PCs are promising drug targets in each disease.

Galacturonosyltransferase (GAUT)1 and GAUT7 are the core of a plant cell wall pectin biosynthetic homogalacturonan:galacturonosyltransferase complex

“…S4 C and D). The GAUT1 aa sequence surrounding this proposed cleavage site is consistent with the consensus motif ([R/K]-[X]n-[R/K], n = 0, 2, 4, or 6) recognized by subtilisin-like proprotein convertases in the secretory pathway (36). Proteolytic cleavage at stem regions by secretory pathway proteases has been documented with many other GTs (29,37).…”

Deciphering the Roles of Tissue Renin-Angiotensin Systems in Whole Animals

“…Furin is a membrane-bound protease that cleaves its substrates in the trans-Golgi network of the secretory pathway of virtually all mammalian cells. 4 Because a fair amount is known about the cleavage preference of furin, 4,5 we were able to design the peptide cleavage site in the fusion protein to be attractive to furin by modifying the natural prorenin prosegment cleavage site (PMKR to RVRTKR; Figure 2A). After cleavage, the encoded peptide is released in the secretory pathway and secreted by the cell ( Figure 2B).…”

“…The selectivity of furin can be deduced in part by examining its natural substrates. 4 This analysis reveals a broad, but finite, array of sequences that can be used in engineering the fusion protein downstream of the furin cleavage site (reviewed in Ref. 5 ).…”

Neuropeptide alterations in the tree shrew hypothalamus during volatile anesthesia

“…The protein is submitted to in silico cleavage according to the following template: (K/R)X m (K/R)X k (K/R)X n (K/R), where X is any amino acid, m and n correspond to 0, 2, 4, 6, and k corresponds to 3-50. The residues X k represent the predicted neuropeptide sequence [23,24] (See the workflow presented in Fig. 1B).…”