10/10 Thank you so much to John Hintze (1st author) and to Katrine for her patience and perseverance that lead to this fabulous and comprehensive work. We were really fortunate and happy to contribute with some cool molecular-level insight. Feedback/Questions are more than welcome 😎
7/10 But what about the effect of hyposialylation of at C6X(3-5)T*C1 (GALNT11) O-glycans?
@silviadandrea.bsky.social ran multiple uncorrelated MD simulations to figure this out using the structure of the RAP/CR5-CR6 complex as a model (PDB 2FYL) with sialylated (and not) core1 at C6-AYP-T-C1
9/10 The presence of sialic acid disrupts the contribution of the glycan to the binding to RAP (b). Interestingly the formation of an intramolecular contact between the core1 and Trp63 during O-glycan maturation could potentially affect its sialylation levels by limiting accessibility to ST3GAL1
Alt: The Office: Michael Scott Bows and Says Thank You
8/10 In the absence of a terminal Sia the Gal of core1 engages in an intramolecular interaction with Trp63 of CR6 (pink in Fig.c and insert), which in turns stabilises the direct contact between the linker and the RAP (red)
2/10 Background: LRP1 is a l~600 kDa transmembrane receptor that engages > 50 different ligands for clearance from neuronal and cerebrospinal fluid (CSF). How this broad ligand selection is accomplished and how it leads to different cellular responses is unclear
5/10 SO, does O-glycosylation of CRs influence LRP1 ligand selection and clearance?
INDEEDLY it does. O-glycosylation significantly enhances uptake of tau and decreases uptake of Aβ in two cell models, HEK293 and neuroblastoma SH-SY5Y cells ⬇️🤯
Next time you hear 'glycans are just a fancy protein decoration' 😱 show them this fabulous work led by Katrine Schjoldager and team at the CGR 🇩🇰 with us 🇬🇧 showing how
The ligand preference of LRP1 is regulated by O-glycans
Out now www.science.org/doi/10.1126/...
🧵1/10 ⬇️
4/10 CRs are O-glycosylated at C6X(3-5)T*C1 by GALNT11, one of 20 GalNAc-transferases that initiate protein GalNAc-type O-glycosylation. O-glycans are present at 13 CR linkers in LRP1 and are hyposialylated
6/10 Interestingly the uptake of RAP, A2M, and ApoE ligands were *unchanged* by the O-glycosylation levels of LRP1, suggesting that CRs O-glycosylation modulates selectively LRP1 recognition and linked functions, not all!
3/10 LRP1 500-kDa soluble subunit (α) has four ligand-binding cysteine-rich complement type repeats (CRs) clusters (I to IV), with 31 CRs in total target different ligands, such as amyloid-β (Aβ), tau, receptor-associated protein (RAP), alpha-2-macroglobulin (A2M), and apolipoprotein E (ApoE)
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GALNT11-mediated O-glycans modulate LRP1 uptake of tau and Aβ, unveiling glycan-driven mechanisms in neurodegenerative pathways.
