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==NMR solution structure of Roseltide rT7== | ==NMR solution structure of Roseltide rT7== | ||
<StructureSection load='6klm' size='340' side='right'caption='[[6klm | <StructureSection load='6klm' size='340' side='right'caption='[[6klm]]' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6klm]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6klm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hibiscus_sabdariffa Hibiscus sabdariffa]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KLM FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 17 models</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6klm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6klm OCA], [https://pdbe.org/6klm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6klm RCSB], [https://www.ebi.ac.uk/pdbsum/6klm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6klm ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Disulfide-rich plant peptides with molecular weights of 2 to 6 kDa represent an expanding class of peptidyl-type natural products with diverse functions. They are structurally compact, hyperstable, and underexplored as cell-penetrating agents that inhibit intracellular functions. Here, we report the discovery of an anionic, 34-residue-peptide, the disulfide-rich roseltide rT7 from Hibiscus sabdariffa (of the Malvaceae family), that penetrates cells and inhibits their proteasomal activities. Combined proteomics and NMR spectroscopy revealed that roseltide rT7 is a cystine-knotted, 6C-hevein-like cysteine-rich peptide. A pair-wise comparison indicated that roseltide rT7 is > 100-fold more stable against protease degradation than its S-alkylated analog. Confocal microscopy studies and cell-based assays disclosed that after roseltide rT7 penetrates cells, it causes accumulation of ubiquitinated proteins, inhibits human 20S proteasomes, reduces tumor necrosis factor-induced IkappaBC; degradation, and decreases expression levels of intercellular adhesion molecule-1. Structure-activity studies revealed that roseltide rT7 uses a canonical substrate-binding mechanism for proteasomal inhibition enabled by an IIML motif embedded in its proline-rich and exceptionally long intercysteine loop 4. Taken together, our results provide mechanistic insights into a novel disulfide-rich, anionic, and cell-penetrating peptide, representing a potential lead for further development as a proteasomal inhibitor in anti-cancer or anti-inflammatory therapies. | |||
Roseltide rT7 is a disulfide-rich, anionic, and cell-penetrating peptide that inhibits proteasomal degradation.,Kam A, Loo S, Fan JS, Sze SK, Yang D, Tam JP J Biol Chem. 2019 Nov 14. pii: RA119.010796. doi: 10.1074/jbc.RA119.010796. PMID:31727740<ref>PMID:31727740</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6klm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Hibiscus sabdariffa]] | [[Category: Hibiscus sabdariffa]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Fan | [[Category: Fan JS]] | ||
[[Category: Kam | [[Category: Kam A]] | ||
[[Category: Loo | [[Category: Loo S]] | ||
[[Category: Tam | [[Category: Tam PJ]] | ||
[[Category: Yang | [[Category: Yang D]] | ||
Latest revision as of 14:09, 30 October 2024
NMR solution structure of Roseltide rT7NMR solution structure of Roseltide rT7
Structural highlights
Publication Abstract from PubMedDisulfide-rich plant peptides with molecular weights of 2 to 6 kDa represent an expanding class of peptidyl-type natural products with diverse functions. They are structurally compact, hyperstable, and underexplored as cell-penetrating agents that inhibit intracellular functions. Here, we report the discovery of an anionic, 34-residue-peptide, the disulfide-rich roseltide rT7 from Hibiscus sabdariffa (of the Malvaceae family), that penetrates cells and inhibits their proteasomal activities. Combined proteomics and NMR spectroscopy revealed that roseltide rT7 is a cystine-knotted, 6C-hevein-like cysteine-rich peptide. A pair-wise comparison indicated that roseltide rT7 is > 100-fold more stable against protease degradation than its S-alkylated analog. Confocal microscopy studies and cell-based assays disclosed that after roseltide rT7 penetrates cells, it causes accumulation of ubiquitinated proteins, inhibits human 20S proteasomes, reduces tumor necrosis factor-induced IkappaBC; degradation, and decreases expression levels of intercellular adhesion molecule-1. Structure-activity studies revealed that roseltide rT7 uses a canonical substrate-binding mechanism for proteasomal inhibition enabled by an IIML motif embedded in its proline-rich and exceptionally long intercysteine loop 4. Taken together, our results provide mechanistic insights into a novel disulfide-rich, anionic, and cell-penetrating peptide, representing a potential lead for further development as a proteasomal inhibitor in anti-cancer or anti-inflammatory therapies. Roseltide rT7 is a disulfide-rich, anionic, and cell-penetrating peptide that inhibits proteasomal degradation.,Kam A, Loo S, Fan JS, Sze SK, Yang D, Tam JP J Biol Chem. 2019 Nov 14. pii: RA119.010796. doi: 10.1074/jbc.RA119.010796. PMID:31727740[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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