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An inducible amphipathic α-helix mediates subcellular targeting and membrane binding of RPE65

View ORCID ProfileSheetal Uppal, Tingting Liu, Emily Galvan, Fatima Gomez, Tishina Tittley, Eugenia Poliakov, Susan Gentleman, View ORCID ProfileT Michael Redmond  Correspondence email
Sheetal Uppal
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing
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  • ORCID record for Sheetal Uppal
Tingting Liu
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Data curation, Formal analysis, Investigation
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Emily Galvan
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Investigation
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Fatima Gomez
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Investigation
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Tishina Tittley
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Investigation
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Eugenia Poliakov
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Conceptualization, Data curation, Formal analysis, Methodology, Writing—review and editing
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Susan Gentleman
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Conceptualization, Writing—review and editing
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T Michael Redmond
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
Roles: Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Writing—review and editing
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  • ORCID record for T Michael Redmond
  • For correspondence: redmondd@nei.nih.gov
Published 20 October 2022. DOI: 10.26508/lsa.202201546
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Abstract

RPE65 retinol isomerase is an indispensable player in the visual cycle between the vertebrate retina and RPE. Although membrane association is critical for RPE65 function, its mechanism is not clear. Residues 107–125 are believed to interact with membranes but are unresolved in all RPE65 crystal structures, whereas palmitoylation at C112 also plays a role. We report the mechanism of membrane recognition and binding by RPE65. Binding of aa107–125 synthetic peptide with membrane-mimicking micellar surfaces induces transition from unstructured loop to amphipathic α-helical (AH) structure but this transition is automatic in the C112-palmitoylated peptide. We demonstrate that the AH significantly affects palmitoylation level, membrane association, and isomerization activity of RPE65. Furthermore, aa107–125 functions as a membrane sensor and the AH as a membrane-targeting motif. Molecular dynamic simulations clearly show AH-membrane insertion, supporting our experimental findings. Collectively, these studies allow us to propose a working model for RPE65-membrane binding, and to provide a novel role for cysteine palmitoylation.

  • Received June 2, 2022.
  • Revision received September 27, 2022.
  • Accepted September 28, 2022.
  • © 2022 Uppal et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Inducible amphipathic α-helix of RPE65
Sheetal Uppal, Tingting Liu, Emily Galvan, Fatima Gomez, Tishina Tittley, Eugenia Poliakov, Susan Gentleman, T Michael Redmond
Life Science Alliance Oct 2022, 6 (1) e202201546; DOI: 10.26508/lsa.202201546

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Inducible amphipathic α-helix of RPE65
Sheetal Uppal, Tingting Liu, Emily Galvan, Fatima Gomez, Tishina Tittley, Eugenia Poliakov, Susan Gentleman, T Michael Redmond
Life Science Alliance Oct 2022, 6 (1) e202201546; DOI: 10.26508/lsa.202201546
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Volume 6, No. 1
January 2023
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