Identification of a Plasmodium falciparum inhibitor‐2 motif involved in the binding and regulation activity of protein phosphatase type 1. (8th September 2014)

• Record Type: Journal Article
• Authors: Fréville, Aline; Tellier, Géraldine; Vandomme, Audrey; Pierrot, Christine; Vicogne, Jérôme; Cantrelle, François‐Xavier; Martoriati, Alain; Cailliau‐Maggio, Katia; Khalife, Jamal; Landrieu, Isabelle
• Is Part Of: FEBS journal. Volume 281:Number 19(2014)
• Page Start: 4519
• Page End: 4534
• Publication Date: 2014-09-08
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.12960
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs12960-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="febs12960-sec-0001" sec-type="section"> <p>The regulation of <italic>Plasmodium falciparum</italic> protein phosphatase type 1 (PfPP1) activity remains to be deciphered. Data from homologous eukaryotic type 1 protein phosphatases (PP1) suggest that several protein regulators should be involved in this essential process. One such regulator, named PfI2 based on its primary sequence homology with eukaryotic inhibitor 2 (I2), was recently shown to be able to interact with PfPP1 and to inhibit its phosphatase activity, mainly through the canonical 'RVxF' binding motif. The details of the structural and functional characteristics of this interaction are investigated here. Using NMR spectroscopy, a second site of interaction is suggested to reside between residues D94 and T117 and contains the 'FxxR/KxR/K' binding motif present in other I2 proteins. This site seems to play in concert/synergy with the 'RVxF' motif to bind PP1, because only mutations in both motifs were able to abolish this interaction completely. However, regarding the structure/function relationship, mutation of either the 'RVxF' or 'FxxR/KxR/K' motif is more drastic, because each mutation prevents the capacity of PfI2 to trigger germinal vesicle breakdown in microinjected <italic>Xenopus</italic> oocytes. This indicates that the tight association of the PfI2 regulator to PP1, mediated by a two‐site interaction, is necessary to exert its function. Based on these results, the use of a peptide derived from the 'FxxR/KxR/K' PfI2 motif was investigated for its potential effect on <italic>Plasmodium</italic> growth. This peptide, fused at its N‐terminus to a penetrating sequence, was shown to accumulate specifically in infected erythrocytes and to have an antiplasmodial effect.</p> </sec> <sec id="febs12960-sec-0002" sec-type="section"> <title>Structured digital abstract</title> <p> <list id="febs12960-list-0001" list-type="bullet"> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q8ILV1" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfPP1</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/C0H480" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfI2</ext-link><ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink"> bind</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0077" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">nuclear magnetic resonance</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9684993" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">1</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9685003" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">2</ext-link>)</p> </list-item> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q8ILV1" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PP1</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">physically interacts</ext-link> with <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/C0H480" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfPP1</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0007" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">anti tag coimmunoprecipitation</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9685042" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">View interaction</ext-link>)</p> </list-item> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/C0H480" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfI2</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">binds</ext-link> to <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q8ILV1" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfPP1</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0411" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">enzyme linked immunosorbent assay</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9685021" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">View interaction</ext-link>)</p> </list-item> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/C0H480" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfI2</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">binds</ext-link> to <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q8ILV1" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">PfPP1</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0107" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">surface plasmon resonance</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9684976" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">1</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9684507" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">2</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9685315" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">3</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9684962" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">4</ext-link>)</p> </list-item> </list> </p> </sec> </abstract>