Cysteine-Rich Peptide Family with Unusual Disulfide Connectivity from Jasminum sambac

Abstract

Cysteine-rich peptides (CRPs) are natural products with privileged peptidyl structures that represent a potentially rich source of bioactive compounds. Here, the discovery and characterization of a novel plant CRP family, jasmintides from Jasminum sambac of the Oleaceae family, are described. Two 27-amino acid jasmintides (jS1 and jS2) were identified at the gene and protein levels. Disulfide bond mapping of jS1 by mass spectrometry and its confirmation by NMR spectroscopy revealed disulfide bond connectivity of C-1-C-5, C-2-C-4, and C-3-C-6, a cystine motif that has not been reported in plant CRPs. Structural determination showed that jS1 displays a well-defined structure framed by three short antiparallel β-sheets. Genomic analysis showed that jasmintides share a three-domain precursor arrangement with a C-terminal mature domain preceded by a long pro-domain of 46 residues and an intron cleavage site between the signal sequence and pro-domain. The compact cysteine-rich structure together with an N-terminal pyroglutamic acid residue confers jasmintides high resistance to heat and enzymatic degradation, including exopeptidase treatment. Collectively, these results reveal a new plant CRP structure with an unusual cystine connectivity, which could be useful as a scaffold for designing peptide drugs.

Lybatides from Lycium barbarum Contain An Unusual Cystine-stapled Helical Peptide Scaffold

“…For example, thionins contain a CC motif at their N-terminus, displaying a cysteine spacing of CC-C-C-C-C-C-C, whereas trans-defensins contain a CC motif at the C-terminus as C-C-C-C-C-C-CC 9 . The presence of the CC motif in the middle can be found in CRPs such as cystine-knot α-amylase inhibitors, hevein-like peptides and jasmintides 13–15 .…”

“…Currently, only three general types of disulfide connectivity are known in plant CRPs. Of the three, the most recently discovered disulfide connectivity, CysI–V, CysII–IV and CysIII–VI, is found in jasmintides 15 . The remaining two are cystine knots represented by defensins, knottins 16 or hevein-like peptides 17 and symmetrics represented by thionins 18 and α-hairpinins 19 .…”

β-Ginkgotides: Hyperdisulfide-constrained peptides from Ginkgo biloba

“…Based on their disulfide connectivities, the CRPs can be broadly classified into two types: cystine knots which are exemplified by knottins, and symmetrics which are represented by thionins 1 . Recently, our laboratory discovered two new families of CRPs with novel disulfide connectivity, the jasmintides 11 and the lybatides. The jasmintides, which contain 27 amino acids with a molecular weight of 3.1 kDa, are six-cysteine CRPs (6C-CRPs) from Jasminum sambac with a disulfide connectivity of CysI‒V, CysII‒IV and CysIII‒VI 11 .…”

Vaccatides: Antifungal Glutamine-Rich Hevein-Like Peptides from Vaccaria hispanica

“…Our interest in the discovery and design of orally active peptides has led us to undertake a program focusing on CRPs in medicinal plants (Tam et al, 1999, 2015; Nguyen et al, 2011a,b, 2012, 2013, 2014, 2015; Kini et al, 2015; Kumari et al, 2015). Plant CRPs, particularly those containing six to ten cysteine residues with molecular weights ranging from 2 to 6 kDa, not only have large footprints required for high pharmacological specificity and selectivity, but are highly disulfide-constrained and structurally compact, properties that provide them high metabolic stability and the potential as orally active compounds (Nguyen et al, 2011a,b, 2012, 2013).…”

“…Recently, our laboratory has characterized a proline-rich subfamily of 8C-hevein-like peptides, ginkgotides from the Ginkgoaceae family of gymnosperm (Wong et al, 2016). The presence of proline flanking both the N-terminus and C-terminus gives the ginkgotides extraordinarily high resistance against degradation by exopeptidases, an added advantage to the known stability of the disulfide-constrained peptides (Nguyen et al, 2011a, 2015; Kumari et al, 2015; Wong et al, 2016). Such stabilities of hevein-like peptides and other plant CRPs qualify them as potential active components in herbal medicines, that normally administrated as decoctions, infusions or teas (Wong et al, 2011; Tam et al, 2015).…”