Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis
| Autor: | Andreas Ebneth, Luke A. Miles, S.J. Hermans, Marie-Laure Rives, Daniel Oehlrich, Berthold Wroblowski, Jasmina Markulić, Michael W. Parker, Ines Royaux, Nancy C. Hancock, Gabriela A. N. Crespi, Andrés A. Trabanco, Jonathan H. Gooi, Larissa Doughty, Tracy L. Nero |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Peptide 02 engineering and technology Molecular neuroscience Alzheimer's Disease Article 03 medical and health sciences chemistry.chemical_compound medicine Receptor lcsh:Science Components of the Immune System chemistry.chemical_classification Multidisciplinary Molecular Structure Microglia 021001 nanoscience & nanotechnology Protein Structure Aspects 3. Good health Sialic acid Cell biology 030104 developmental biology medicine.anatomical_structure chemistry lcsh:Q CD33 Molecular Neuroscience Small molecule binding Pharmacophore 0210 nano-technology Glycoprotein Neuroscience |
| Zdroj: | iScience, Vol 19, Iss, Pp 110-118 (2019) iScience |
| ISSN: | 2589-0042 |
| Popis: | Summary Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer disease (AD), and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Progress toward discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity toward sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, amyloid-β (Aβ), into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aβ peptide that is thought to cause AD. Graphical Abstract Highlights • A sialic acid mimetic increases the uptake of Alzheimer peptide into microglia • Crystal structure of cell surface receptor CD33 bound to the sialic acid mimetic • Crystal structure of unliganded CD33 and mutagenesis studies revealed key residues • CD33 carbohydrate-binding site is a pharmacophore for Alzheimer drug development Molecular Structure; Neuroscience; Molecular Neuroscience; Components of the Immune System; Protein Structure Aspects |
| Databáze: | OpenAIRE |
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