The structure of<i>Plasmodium vivax</i>phosphatidylethanolamine-binding protein suggests a functional motif containing a left-handed helix

Arakaki, T.L.; Neely, H.; Boni, Erica; Mueller, Natasha; Buckner, Frederick S.; Voorhis, Wesley C. Van; Lauricella, Angela; DeTitta, George T.; Luft, Joseph R.; Hól, Wim G. J.; Merritt, E.A.

doi:10.1107/s1744309107007580

Cited by 6 publications

(4 citation statements)

References 36 publications

(42 reference statements)

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“…A right‐handed helix formation in all D‐amino acid peptide may have some energy penalty, but if this penalty is compensated by packing with its cognate binding protein the right‐handed helix formation may be feasible. In comparison, the left‐handed helical conformation is less energetically favorable in natural proteins (all L‐amino acid), however, left‐handed helical conformations are sometimes found in small segments of proteins in which they are packed with other stable secondary structures (30,31). The left‐handed helix conformation does not exist in the prohibited region of the Ramachandran plot, but it occurs in a very constricted allowed region.…”

Section: Discussionmentioning

confidence: 99%

Research Letter: Retroinverso Mimetics of S Peptide

Rai¹

2007

Chem Biol Drug Des

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The S peptide from ribonuclease S was used as a model system to explore the relationship between the native peptide and its retroinverso (RI) analog. As probed by circular dichroism, the conformations of S peptide and retroinverso S peptide (RIS peptide) are each right-handed helical conformation. The helical propensity of retro S peptide is greater than S peptide, in trifluoroethanol (TFE). In 70% TFE, the S peptide possesses greater helicity at pH 4 than at pH 7, whereas RIS peptide possesses greater helicity at pH 7 than at pH 4. The RIS peptide does not mimic the S peptide in binding to S protein. Specifically, the RIS peptide does not mimic the S peptide to effect RNase activity with S protein and it also does not inhibit the RNase activity of S peptide with S protein. The biological mimicry between the S peptide and its RIS analog depends on the conformation and relatedness of both the side chain and backbone substructures. The backbones in the S peptide and its RIS analog are reverted with respect to each other; however, the side chain patterns are predicted to be similar. Importantly, if the molecular interactions of backbone atoms of the S peptide and its binding to S protein, then the RIS analog would be unlikely to mimic this parent peptide.

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Section: Discussionmentioning

confidence: 99%

Research Letter: Retroinverso Mimetics of S Peptide

Rai¹

2007

Chem Biol Drug Des

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“…Conserved residues in PEBP domain of PfRKIP are important for its interaction with lipids Like other PEBP domain containing proteins, PfRKIP contain motifs that are important for interaction with lipids and other partner proteins [16,24](Fig. 3a).…”

Section: Pfrkip Show Ph Dependent Distinct Interaction Profile With L...mentioning

confidence: 99%

“…Histidine residue at corresponding position in HsRKIP is important for interaction with other proteins [25]. In P. vivax, RKIP contains a rare left-handed α-helix, α5 that is present near the ligand binding site and is postulated to have a role during recognition of phospholipids [24]. A similar left-handed α-helix is also present at the corresponding position in PfRKIP that we selected for disruption to study its role in lipid binding.…”

Section: Pfrkip Show Ph Dependent Distinct Interaction Profile With L...mentioning

confidence: 99%

Plasmodium falciparumRaf kinase inhibitor is a lipid binding protein that interacts with CDPK1 and regulates its activity in asexual blood stage

Sharma,

Krishnan,

Negi

et al. 2023

Preprint

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Raf Kinase Inhibitor Protein (RKIP) is an important regulator of MAPK signaling pathway in multicellular eukaryotes. Plasmodium falciparum RKIP (PfRKIP) is a putative phosphatidylethanolamine binding protein (PEBP) that shares limited similarity with Homo sapiens RKIP (HsRKIP). Interestingly, critical components of MAPK pathway are not expressed in malaria parasite and the physiological function of PfRKIP remains unknown. PfRKIP is expressed throughout the asexual schizogony with maximum expression in late schizonts. Interestingly, PfRKIP and HsRKIP show pH dependent differential interaction profiles with various lipids. At physiological pH, PfRKIP show interaction with PE and lipids containing phosphorylated phosphatidylinositol group; however, HsRKIP show no interaction under the same conditions. Mutation of conserved residues in the PEBP domain of PfRKIP decreases its interaction with PI(3)P. Furthermore, our results suggest that PfRKIP leads to increase in the autophosphorylation of PfCDPK1 that leads to transphosphorylation of substrates by PfCDPK1. Using various in vitro and in vivo experiments we have demonstrated the interaction of PfRKIP with PfCDPK1 and have also identified key residues in PfRKIP that play important role in this interaction. Interestingly, locostatin, a specific inhibitor of mammalian RKIP increased the interaction of PfRKIP with PfCDPK1 that perhaps leads to the sequestration of PfCDPK1 in a heterodimeric complex. Importantly, treatment of malaria parasite with locostatin shows dose dependent inhibition of parasite growth. This study suggests that specific inhibitors that modify PfRKIP leading to increase in its interaction with PfCDPK1 may be designed and explored as novel anti-malarial compounds to inhibit malaria parasite growth.

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“…43 With few exceptions, PEBP proteins from diverse species have been found to be relatively easy to express and crystallize, leading to the publication of numerous structures, including those from plants, bacteria, yeast, and the protozoal parasite Plasmodium . 44–47 The small size of the proteins has also enabled recent NMR structural studies. 48–50 …”

Section: Structural Studiesmentioning

confidence: 99%

Phosphatidylenthanolamine Binding Protein aka Raf Kinase Inhibitor Protein: A Brief History of Its Discovery and the Remarkable Diversity of Biological Functions

Sedivy

2011

Forum Immun Dis Ther

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Phosphatidylethanolamine-binding protein (PEBP) was identified almost three decades ago as an abundant protein in bovine brain. PEBP is the prototype of a highly conserved family of proteins represented in all three major phylogenetic divisions, eukaryota, bacteria, and archaea, with no significant sequence homology to other proteins. PEBP proteins have been studied in many species. The most thoroughly explored biological role of PEBP is that of a modulator of intracellular signaling pathways, which is mediated by its ability to bind and inhibit a number of protein kinases. The first such interaction that came to light was with the Raf1 kinase, and PEBP is thus widely referred to in the literature under its alternate name RKIP (Raf kinase inhibitory protein). The activity of RKIP itself is subject to regulation by phosphorylation. Intriguingly, PEBP has also been reported to possess additional, and diverse, biological functions unrelated to protein kinase networks that remain to be investigated in detail. Recent findings that RKIP may function as a suppressor of cancer metastasis are of great interest and importance. Prognostic and therapeutic applications of RKIP in human cancer were the subject of the first international workshop on RKIP that was held at the University of California, Los Angeles, in March 2010. This paper was presented at the workshop as a summary of the history of this still small but rapidly evolving field.

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The structure ofPlasmodium vivaxphosphatidylethanolamine-binding protein suggests a functional motif containing a left-handed helix

Cited by 6 publications

References 36 publications

Research Letter: Retroinverso Mimetics of S Peptide

Research Letter: Retroinverso Mimetics of S Peptide

Plasmodium falciparumRaf kinase inhibitor is a lipid binding protein that interacts with CDPK1 and regulates its activity in asexual blood stage

Phosphatidylenthanolamine Binding Protein aka Raf Kinase Inhibitor Protein: A Brief History of Its Discovery and the Remarkable Diversity of Biological Functions

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