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dc.contributor.authorIqbal, Sameera
dc.contributor.authorWalsh, Tiffany R
dc.contributor.authorRodger, Alison
dc.contributor.authorPacker, Nicolle H
dc.date.accessioned2021-06-04T06:17:46Z
dc.date.available2021-06-04T06:17:46Z
dc.date.issued2020
dc.identifier.issn1948-7193
dc.identifier.doi10.1021/acschemneuro.0c00139
dc.identifier.urihttp://hdl.handle.net/10072/404950
dc.description.abstractPolysialic acid (polySia) is a highly negatively charged linear homopolymer comprising α-2,8-linked sialic acids. It is abundant in the embryonic brain and modulates various functions such as differentiation and synaptic plasticity in the adult central nervous system by direct binding to its protein partners. One such example is the binding of polySia to myristoylated-alanine rich C-kinase substrate (MARCKS) to modulate neuritogenesis. To understand their interaction mechanism at the molecular level, we performed a binding assay which showed a direct binding of the MARCKS-ED peptide (KKKKKRFSFKKSFKLSGFSFKKNKK) with polySia in a concentration-dependent manner. Molecular dynamics simulations revealed that this binding is not exclusively dominated by electrostatics but can in part be attributed to the presence of near-regularly spaced Phe residues, that confer a compact 3D conformation based on pseudoglycine loop structures supported by Phe-Phe interactions. Our simulations, which are confirmed by circular dichroism measurements, also indicate that the peptide-polySia binding induces large-scale conformational rearrangement of polySia into coils at the binding site, whereas the peptide conformation is relatively unperturbed. As a consequence, we predict that each peptide can bind to a domain extending ∼14 polySia repeat units. Using the fluorescently tagged MARCKS-ED peptide on rat brainstem tissue sections, we demonstrate the ability of the peptide to detect polySia, similarly to polySia-specific antibody mAb735, especially in the spinal trigeminal nucleus and the dorsal vagal complex. This study provides information about the interaction between polySia and its CNS protein binding partner, MARCKS, and provides a fundamental platform for further studies to explore the prospect of the MARCKS-ED as an effective polySia-binding peptide for bioimaging and drug delivery applications.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherAmerican Chemical Society (ACS Publications)
dc.relation.ispartofpagefrom1944
dc.relation.ispartofpageto1954
dc.relation.ispartofissue13
dc.relation.ispartofjournalACS Chemical Neuroscience
dc.relation.ispartofvolume11
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchcode0304
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiochemistry & Molecular Biology
dc.subject.keywordsChemistry, Medicinal
dc.subject.keywordsNeurosciences
dc.titleInteraction between Polysialic Acid and the MARCKS-ED Peptide at the Molecular Level
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationIqbal, S; Walsh, TR; Rodger, A; Packer, NH, Interaction between Polysialic Acid and the MARCKS-ED Peptide at the Molecular Level, ACS Chemical Neuroscience, 2020, 11 (13), pp. 1944-1954
dc.date.updated2021-06-04T06:16:57Z
gro.hasfulltextNo Full Text
gro.griffith.authorPacker, Nicki


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