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A new gating site in human aquaporin-4: Insights from molecular dynamics simulations.

Giuseppe Felice Mangiatordi; Antonio Frigeri; Orazio Nicolotti; Gianluca Lattanzi; Francesco Pisani; Valentina Benfenati; Domenico Alberga; Grazia Paola Nicchia


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  <identifier identifierType="URL">https://www.openaccessrepository.it/record/135817</identifier>
  <creators>
    <creator>
      <creatorName>Giuseppe Felice Mangiatordi</creatorName>
    </creator>
    <creator>
      <creatorName>Antonio Frigeri</creatorName>
    </creator>
    <creator>
      <creatorName>Orazio Nicolotti</creatorName>
    </creator>
    <creator>
      <creatorName>Gianluca Lattanzi</creatorName>
    </creator>
    <creator>
      <creatorName>Francesco Pisani</creatorName>
    </creator>
    <creator>
      <creatorName>Valentina Benfenati</creatorName>
    </creator>
    <creator>
      <creatorName>Domenico Alberga</creatorName>
    </creator>
    <creator>
      <creatorName>Grazia Paola Nicchia</creatorName>
    </creator>
  </creators>
  <titles>
    <title>A new gating site in human aquaporin-4: Insights from molecular dynamics simulations.</title>
  </titles>
  <publisher>INFN Open Access Repository</publisher>
  <publicationYear>2014</publicationYear>
  <subjects>
    <subject>Cell Biology</subject>
    <subject>Biochemistry</subject>
    <subject>Biophysics</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2014-12-01</date>
  </dates>
  <language>en</language>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://www.openaccessrepository.it/record/135817</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1016/j.bbamem.2014.08.015</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://www.openaccessrepository.it/communities/itmirror</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="info:eu-repo/semantics/closedAccess">Closed Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">AbstractAquaporin-4 (AQP4) is the predominant water channel in different organs and tissues. An alteration of its physiological functioning is responsible for several disorders of water regulation and, thus, is considered an attractive target with a promising therapeutic and diagnostic potential. Molecular dynamics (MD) simulations performed on the AQP4 tetramer embedded in a bilayer of lipid molecules allowed us to analyze the role of spontaneous fluctuations occurring inside the pore. Following the approach by Hashido et al. [Hashido M, Kidera A, Ikeguchi M (2007) Biophys J 93: 373–385], our analysis on 200ns trajectory discloses three domains inside the pore as key elements for water permeation. Herein, we describe the gating mechanism associated with the well-known selectivity filter on the extracellular side of the pore and the crucial regulation ensured by the NPA motifs (asparagine, proline, alanine). Notably, on the cytoplasmic side, we find a putative gate formed by two residues, namely, a cysteine belonging to the loop D (C178) and a histidine from loop B (H95). We observed that the spontaneous reorientation of the imidazole ring of H95 acts as a molecular switch enabling H-bond interaction with C178. The occurrence of such local interaction seems to be responsible for the narrowing of the pore and thus of a remarkable decrease in water flux rate. Our results are in agreement with recent experimental observations and may represent a promising starting point to pave the way for the discovery of chemical modulators of AQP4 water permeability.</description>
  </descriptions>
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