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Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

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Wang, S, Mao, Y, Narimatsu, Y, Ye, Z, Tian, W, Goth, CK, Lira-Navarrete, E, Pedersen, NB, Benito-Vicente, A, Martin, C, Uribe, KB, Hurtado-Guerrero, R, Christoffersen, C, Seidah, NG, Nielsen, R, Christensen, EI, Hansen, L, Bennett, EP, Vakhrushev, SY, Schjoldager, KT & Clausen, H 2018, 'Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions' The journal of biological chemistry, vol. 293, no. 19, pp. 7408-7422. https://doi.org/10.1074/jbc.M117.817981

APA

CBE

Wang S, Mao Y, Narimatsu Y, Ye Z, Tian W, Goth CK, Lira-Navarrete E, Pedersen NB, Benito-Vicente A, Martin C, Uribe KB, Hurtado-Guerrero R, Christoffersen C, Seidah NG, Nielsen R, Christensen EI, Hansen L, Bennett EP, Vakhrushev SY, Schjoldager KT, Clausen H. 2018. Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions. The journal of biological chemistry. 293(19):7408-7422. https://doi.org/10.1074/jbc.M117.817981

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Author

Wang, Shengjun ; Mao, Yang ; Narimatsu, Yoshiki ; Ye, Zilu ; Tian, Weihua ; Goth, Christoffer K ; Lira-Navarrete, Erandi ; Pedersen, Nis B ; Benito-Vicente, Asier ; Martin, Cesar ; Uribe, Kepa B ; Hurtado-Guerrero, Ramon ; Christoffersen, Christina ; Seidah, Nabil G ; Nielsen, Rikke ; Christensen, Erik I ; Hansen, Lars ; Bennett, Eric P ; Vakhrushev, Sergey Y ; Schjoldager, Katrine T ; Clausen, Henrik. / Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions. In: The journal of biological chemistry. 2018 ; Vol. 293, No. 19. pp. 7408-7422.

Bibtex

@article{50ef5a14d00b4e97b6971ec8ac760cae,
title = "Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions",
abstract = "The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11-mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by ∼5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease.",
author = "Shengjun Wang and Yang Mao and Yoshiki Narimatsu and Zilu Ye and Weihua Tian and Goth, {Christoffer K} and Erandi Lira-Navarrete and Pedersen, {Nis B} and Asier Benito-Vicente and Cesar Martin and Uribe, {Kepa B} and Ramon Hurtado-Guerrero and Christina Christoffersen and Seidah, {Nabil G} and Rikke Nielsen and Christensen, {Erik I} and Lars Hansen and Bennett, {Eric P} and Vakhrushev, {Sergey Y} and Schjoldager, {Katrine T} and Henrik Clausen",
note = "{\circledC} 2018 by The American Society for Biochemistry and Molecular Biology, Inc.",
year = "2018",
month = "5",
day = "11",
doi = "10.1074/jbc.M117.817981",
language = "English",
volume = "293",
pages = "7408--7422",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc",
number = "19",

}

RIS

TY - JOUR

T1 - Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

AU - Wang, Shengjun

AU - Mao, Yang

AU - Narimatsu, Yoshiki

AU - Ye, Zilu

AU - Tian, Weihua

AU - Goth, Christoffer K

AU - Lira-Navarrete, Erandi

AU - Pedersen, Nis B

AU - Benito-Vicente, Asier

AU - Martin, Cesar

AU - Uribe, Kepa B

AU - Hurtado-Guerrero, Ramon

AU - Christoffersen, Christina

AU - Seidah, Nabil G

AU - Nielsen, Rikke

AU - Christensen, Erik I

AU - Hansen, Lars

AU - Bennett, Eric P

AU - Vakhrushev, Sergey Y

AU - Schjoldager, Katrine T

AU - Clausen, Henrik

N1 - © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2018/5/11

Y1 - 2018/5/11

N2 - The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11-mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by ∼5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease.

AB - The low-density lipoprotein receptor (LDLR) and related receptors are important for the transport of diverse biomolecules across cell membranes and barriers. Their functions are especially relevant for cholesterol homeostasis and diseases, including neurodegenerative and kidney disorders. Members of the LDLR-related protein family share LDLR class A (LA) repeats providing binding properties for lipoproteins and other biomolecules. We previously demonstrated that short linker regions between these LA repeats contain conserved O-glycan sites. Moreover, we found that O-glycan modifications at these sites are selectively controlled by the GalNAc-transferase isoform, GalNAc-T11. However, the effects of GalNAc-T11-mediated O-glycosylation on LDLR and related receptor localization and function are unknown. Here, we characterized O-glycosylation of LDLR-related proteins and identified conserved O-glycosylation sites in the LA linker regions of VLDLR, LRP1, and LRP2 (Megalin) from both cell lines and rat organs. Using a panel of gene-edited isogenic cell line models, we demonstrate that GalNAc-T11-mediated LDLR and VLDLR O-glycosylation is not required for transport and cell-surface expression and stability of these receptors but markedly enhances LDL and VLDL binding and uptake. Direct ELISA-based binding assays with truncated LDLR constructs revealed that O-glycosylation increased affinity for LDL by ∼5-fold. The molecular basis for this observation is currently unknown, but these findings open up new avenues for exploring the roles of LDLR-related proteins in disease.

U2 - 10.1074/jbc.M117.817981

DO - 10.1074/jbc.M117.817981

M3 - Journal article

VL - 293

SP - 7408

EP - 7422

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 19

ER -

ID: 55708927