Structural requirements for processing of pro‐adipokinetic hormone I

Rayne, Richard C.; O’Shea, Michael

doi:10.1111/j.1432-1033.1993.tb18320.x

Cited by 17 publications

(5 citation statements)

References 32 publications

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“…These data, supported by the study of the processing domain OT/Np(1-20) [59], reveal the presence of b-turn structure in the vicinity of the dibasic cleavage site. These conclusions, confirmed by different studies conducted on the OT/Np [60], Adipokinetic hormone [61] and insulin [62] precursors, support the concept that b-turn structures constitute recognition signals for the processing endoproteases [2,43].…”

supporting

confidence: 84%

Processing of peptide and hormone precursors at the dibasic cleavage sites

Rholam

Fahy

2009

Cell. Mol. Life Sci.

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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.

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supporting

confidence: 84%

Processing of peptide and hormone precursors at the dibasic cleavage sites

Rholam

Fahy

2009

Cell. Mol. Life Sci.

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“…Earlier analysis of amino acid sequences around proteolytic cleavage sites of several biosynthetic precursors by secondary structure predictive methods (31) indicated that the dibasic residues constituting these cleavage sites are located in or immediately adjacent to regions with high β-turn formation propensity (3,31,53). Site-directed mutagenesis of prohormone cDNA coupled with spectroscopic and enzymatic studies of substrates reproducing the cleavage loci of various prohormones have shown that these β-turn structures situated in the vicinity of dibasic cleavage sites (16,(54)(55)(56)(57)(58) constitute an essential feature for the processing of precursors (14,36,54,57).…”

Section: Discussionmentioning

confidence: 99%

The Somatostatin-28(1−12)-NPAMAP Sequence: An Essential Helical-Promoting Motif Governing Prosomatostatin Processing at Mono- and Dibasic Sites

et al. 2002

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Proline residues, known to have special structural properties, induce particular conformations which participate in some biological functions. Two prolines (Pro(-9), Pro(-5)) located near the processing sites (Arg(-15) and Arg(-2)Lys(-)(1)) of human prosomatostatin were previously shown to be important for cleavage of the precursor into somatostatin-28 (S-28) and somatostatin-14 (S-14) [Gomez et al. (1989) EMBO J. 8, 2911-2916]. In this study, the importance of the pentapeptide P-A-M-A-P sequence (P-(X)(3)-P pattern), located in the S-28(1-12) segment connecting the mono- and dibasic cleavage sites, was investigated by using site-directed mutagenesis. Analysis of prosomatostatin-derived peptides produced by expression of mutated cDNA species in Neuro2A cells indicated that (i) deletion of PAMAP decreased S-14 production, (ii) deletion of the two Pro residues almost abolished the cleavage at the dibasic site, and (iii) Pro displacement generating the AMAPP motif resulted in a decrease of S-28 production. Moreover, both theoretical and spectroscopic studies of synthetic peptides reproducing the S-28(1-12) sequence bearing critical mutations showed that this sequence can organize as an alpha helical structure. These observations demonstrate that NPAMAP constitutes an accurate alpha-helix nucleation motif allowing for the generation of equal amounts of S-28 and S-14 from their common precursor in Neuro2A cells. Moreover, they emphasize the importance of the S-28(1-12) segment joining Arg(-15) and Arg(-2)Lys(-1) cleavage sites whose conformational organization is essential for controlling their accessibility to the appropriate processing proteases.

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“…In the case of prohormones, it has been postulated that amino acid flanking dibasic cleavage sites and secondary structures may direct endoprotease to the appropriate sites ( − ). Studies conducted with short peptides reproducing cleavage sites of prosomatostatin and of prooxytocin/neurophysin have shown that the sequences flanking the basic amino acid doublets might participate in the recognition of the cleavage site by providing accessible peptide segments constituted by β-turns () or Ω-loops ( , ) and may indeed play a role in the processing ( , ). From these studies, it was assumed that such structures, which are flexible and mobile, favor both the accessibility and the segmental adaptability when compared with other structures such as α-helices or β-sheets.…”

Section: Discussionmentioning

confidence: 99%

Retroviral Envelope Glycoprotein Processing: Structural Investigation of the Cleavage Site

Moulard¹,

Chaloin²,

Canarelli³

et al. 1998

Biochemistry

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Proteolytic activation of retroviral envelope glycoprotein precursors occurs at the carboxyl side of a consensus motif consisting of the amino acid sequence (Arg/Lys)-Xaa-(Arg/Lys)-Arg. Synthetic peptides spanning the processing sites of HIV-1/2 and SIV glycoprotein precursors were examined for their ability to be cleaved by the subtilisin-like endoproteases kexin and furin. To determine the potential role of secondary structure on proteolytic activation, we examined the secondary structure of synthetic peptides by circular dichroism and NMR spectroscopy. The results indicate that (i) the peptides were correctly cleaved by kexin and furin and therefore could be used as specific substrates for the purification and characterization of the lymphocyte endoprotease(s) responsible for proteolytic processing of precursors; (ii) the regions surrounding the cleavage sites could be characterized by their flexibility in aqueous solutions. However, a loop has been shown to be a determinant for the specificity of the interaction between the enzyme and its substrate as determined by molecular modeling. Furthermore, we determine and propose a possible structure of the cleavage site which fits to the active site of the modeled furin.

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Structural requirements for processing of pro‐adipokinetic hormone I

Cited by 17 publications

References 32 publications

Processing of peptide and hormone precursors at the dibasic cleavage sites

Processing of peptide and hormone precursors at the dibasic cleavage sites

The Somatostatin-28(1−12)-NPAMAP Sequence: An Essential Helical-Promoting Motif Governing Prosomatostatin Processing at Mono- and Dibasic Sites

Retroviral Envelope Glycoprotein Processing: Structural Investigation of the Cleavage Site

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