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      Divalent Cations and Lipid Composition Modulate Membrane Insertion and Cancer-Targeting Action of pHLIP

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      Journal of Molecular Biology
      Elsevier BV

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          Abstract

          <p class="first" id="P3">The pH-Low Insertion Peptide (pHLIP) has emerged as an important tool for targeting cancer cells; it has been assumed that its targeting mechanism depends solely on the mild acidic environment surrounding tumors. Here, we examine the role of Ca <sup>2+</sup> and Mg <sup>2+</sup> on pHLIP’s insertion, cellular targeting and drug delivery. We demonstrate that physiologically-relevant concentrations of either cation can shift the protonation-dependent transition by up to several pH units towards basic pH and induce substantial protonation-independent transmembrane insertion of pHLIP at pH as high as 10. Consistent with these results, the ability of pHLIP to deliver the cytotoxic compound monomethyl-auristatin-F to HeLa cells is increased several-fold in presence of Ca <sup>2+</sup>. Complementary measurements with model membranes confirmed this Ca <sup>2+</sup>/Mg <sup>2+</sup>-dependent membrane-insertion mechanism. The magnitude of this alternative Ca <sup>2+</sup>/Mg <sup>2+</sup>-dependent effect is also modulated by lipid composition—specifically by the presence of phosphatidylserine—providing new clues to pHLIP’s unique tumor targeting ability in vivo. These results exemplify the complex coupling between protonation of anionic residues and lipid-selective targeting by divalent cations, which is relevant to the general signaling on membrane interfaces. </p><p id="P4"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/92901b7a-45a6-400e-b342-2568510095bb/PubMedCentral/image/nihms-1544579-f0007.jpg"/> </div> </p>

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          Author and article information

          Journal
          Journal of Molecular Biology
          Journal of Molecular Biology
          Elsevier BV
          00222836
          November 2019
          November 2019
          Article
          10.1016/j.jmb.2019.10.016
          6920566
          31689432
          7586e087-e4bf-4ed9-8935-fc794f7e55a0
          © 2019

          https://www.elsevier.com/tdm/userlicense/1.0/

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