Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

Author:

Schmidt Edward N.,Lamprinaki Dimitra,McCord Kelli A.ORCID,Joe MajuORCID,Sojitra MiratORCID,Waldow Ayk,Nguyen JasmineORCID,Monyror JohnORCID,Kitova Elena N.ORCID,Mozaneh Fahima,Guo Xue Yan,Jung Jaesoo,Enterina Jhon R.,Daskhan Gour C.,Han Ling,Krysler Amanda R.ORCID,Cromwell Christopher R.ORCID,Hubbard Basil P.ORCID,West Lori J.ORCID,Kulka MarianneORCID,Sipione Simonetta,Klassen John S.,Derda RatmirORCID,Lowary Todd L.ORCID,Mahal Lara K.ORCID,Riddell Meghan R.ORCID,Macauley Matthew S.ORCID

Abstract

AbstractImmunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec–glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles. These results demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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