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Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Fernandez-Castaneda, Anthony, Arandjelovic, Sanja, Stiles, Travis L., Schlobach, Ryan K., Mowen, Kerri A., Gonias, Steven L., Gaultier, Alban·2013·Journal of Biological Chemistry
DOI 10.1074/jbc.m112.384693
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FIGURE 1 CCRII and CCRIV bind LRP1 ligands. A , schematic representation of LRP1 and CCRII and CCRIV constructs. B , Fc, CCRII, and CCRIV were incubatedwithGST-RAPasdescribedunder'ExperimentalProcedures,' and GSTRAP was recovered by incubation with glutathione-agarose beads. Samples and purified proteins were analyzed by Coomassie staining. C , Fc, CCRII, and CCRIVwereincubatedwithmyelinproteinextract in the presence or absence of GST-RAP. Fc and CCRs were recovered by adding protein A-agarose beads. Samples were analyzed by Coomassie staining.
FIGURE 1 CCRII and CCRIV bind LRP1 ligands. A , schematic representation of LRP1 and CCRII and CCRIV constructs. B , Fc, CCRII, and CCRIV were incubatedwithGST-RAPasdescribedunder'ExperimentalProcedures,' and GSTRAP was recovered by incubation with glutathione-agarose beads. Samples and purified proteins were analyzed by Coomassie staining. C , Fc, CCRII, and CCRIVwereincubatedwithmyelinproteinextract in the presence or absence of GST-RAP. Fc and CCRs were recovered by adding protein A-agarose beads. Samples were analyzed by Coomassie staining.CC-BY · From the PDF
FIGURE2 Identification of LRP1 CCR ligands. A , myelin proteins interacting with LRP1 CCRs were as follows: Cnp , CNP; Sept7 , septin-7; Mtap1b , microtubule-associated protein-1b; Sept2 , septin-2; Sept8 , septin-8; Padi2 , PAD2; Mtap1a , microtubule-associated protein-1a; Plcb1 , phosphatidylinositol-bisphosphate phosphodiesterase 𝛃 -1; Sept4 , septin-4; Glul , glutamine synthetase. B , endogenousproteinsassociating with LRP1 CCR were as follows: Glg1 , Golgi glycoprotein-1; Lgmn , legumain; Timp2 , tissue inhibitor of metalloproteinase-2; Sparc , secreted protein acidic and rich in cysteine; Fhl1 , four and a half LIM domains protein 1; Mmp19 , matrix metalloproteinase-19; Hpse , heparanase; Mmp9 , matrix metalloproteinase-9; Fcho2 , FCH domain only protein-2; Col5a2 , collagen 5.
FIGURE2 Identification of LRP1 CCR ligands. A , myelin proteins interacting with LRP1 CCRs were as follows: Cnp , CNP; Sept7 , septin-7; Mtap1b , microtubule-associated protein-1b; Sept2 , septin-2; Sept8 , septin-8; Padi2 , PAD2; Mtap1a , microtubule-associated protein-1a; Plcb1 , phosphatidylinositol-bisphosphate phosphodiesterase 𝛃 -1; Sept4 , septin-4; Glul , glutamine synthetase. B , endogenousproteinsassociating with LRP1 CCR were as follows: Glg1 , Golgi glycoprotein-1; Lgmn , legumain; Timp2 , tissue inhibitor of metalloproteinase-2; Sparc , secreted protein acidic and rich in cysteine; Fhl1 , four and a half LIM domains protein 1; Mmp19 , matrix metalloproteinase-19; Hpse , heparanase; Mmp9 , matrix metalloproteinase-9; Fcho2 , FCH domain only protein-2; Col5a2 , collagen 5.CC-BY · From the PDF
Image 3
CC-BY · From the PDF
FIGURE 4 PAD2 and CNP interact with full-length LRP1. A , PAD2-His and GST-CNPwereexpressed as fusion proteins in bacteria and subjected to SDSPAGE with Coomassie staining. B , BSA, FN (Fibronectin), and LRP1 were adsorbed onto plastic wells and incubated with purified PAD2-His. PAD2 binding to the immobilized phase was detected in an ELISA format, using anti-PAD2 serum, as described under 'Experimental Procedures.' ***, p < 0.001. C , BSA, GST, GST-CNP, and GST-RAP were adsorbed onto plastic wells as described under 'Experimental Procedures' and incubated with soluble human LRP1. LRP1 binding to the immobilized phase was detected in an ELISA format, using LRP1 𝛂 -chain-specific antibody 8G1. ***, p < 0.001.
FIGURE 4 PAD2 and CNP interact with full-length LRP1. A , PAD2-His and GST-CNPwereexpressed as fusion proteins in bacteria and subjected to SDSPAGE with Coomassie staining. B , BSA, FN (Fibronectin), and LRP1 were adsorbed onto plastic wells and incubated with purified PAD2-His. PAD2 binding to the immobilized phase was detected in an ELISA format, using anti-PAD2 serum, as described under 'Experimental Procedures.' ***, p < 0.001. C , BSA, GST, GST-CNP, and GST-RAP were adsorbed onto plastic wells as described under 'Experimental Procedures' and incubated with soluble human LRP1. LRP1 binding to the immobilized phase was detected in an ELISA format, using LRP1 𝛂 -chain-specific antibody 8G1. ***, p < 0.001.CC-BY · From the PDF
FIGURE 5 LRP1 is a substrate for PAD2-mediated citrullination. A , RAW264.7 cell extracts were incubated with or without purified PAD2 and CaCl2 , as described under 'Experimental Procedures.' LRP1 was then purified using GST-RAP pulldown. Samples and input were analyzed by immunoblotting ( IB ) using LRP1 𝛂 -chain-specific antibody or with an antibody specific for citrullinated proteins. Grp78 immunoblot was used as a control of protein load. B , brain protein extract was incubated with or without CaCl 2 , or with CaCl2 and purified PAD2, as described under 'Experimental Procedures.' LRP1 was then purified using GST-RAP pulldown. Samples and input were analyzedbyimmunoblottingusingLRP1 𝛂 -chain-specific antibody or with an antibody specific for citrullinated proteins.
FIGURE 5 LRP1 is a substrate for PAD2-mediated citrullination. A , RAW264.7 cell extracts were incubated with or without purified PAD2 and CaCl2 , as described under 'Experimental Procedures.' LRP1 was then purified using GST-RAP pulldown. Samples and input were analyzed by immunoblotting ( IB ) using LRP1 𝛂 -chain-specific antibody or with an antibody specific for citrullinated proteins. Grp78 immunoblot was used as a control of protein load. B , brain protein extract was incubated with or without CaCl 2 , or with CaCl2 and purified PAD2, as described under 'Experimental Procedures.' LRP1 was then purified using GST-RAP pulldown. Samples and input were analyzedbyimmunoblottingusingLRP1 𝛂 -chain-specific antibody or with an antibody specific for citrullinated proteins.CC-BY · From the PDF
Image 6
CC-BY · From the PDF
FIGURE 7 LRP1 is a phagocytic receptor for necrotic cells. A , annexin 5/7-amino-actinomycin D ( 7AAD ) staining of live and necrotic Jurkat cells. B , phase contrast microscopy of live and necrotic N20.1 cells. C , CFSE-labeled LRP1 positive or negative fibroblasts were incubated with live or necrotic CypHer-labeled Jurkat cells for 2 h. After washing, fibroblast-associated CypHer fluorescence was analyzed by flow cytometry. D , results are normalized to the difference of CypHermedianfluorescencebetweenLRP1-positivecellsincubatedwithnecroticcellsanduntreatedLRP1-positivecells(arepresentativeoftwoindependent experimentsis shown; ****, p < 0.0001). E , BV2 cells were incubated with live or necrotic CypHer-labeled N20.1 cells for 30 min. After washing, BV2 were stained with CD11b-Alexa Fluor 488 antibody and BV2-associated CypHer fluorescence was analyzed by flow cytometry. F , results are normalized to the difference of CypHermedianfluorescencebetweenGSTtreatedcellsincubatedwithnecroticcellsanduntreatedBV2cells(arepresentativeofsixindependentexperiments is shown). ***, p < 0.001. ns , not significant.
FIGURE 7 LRP1 is a phagocytic receptor for necrotic cells. A , annexin 5/7-amino-actinomycin D ( 7AAD ) staining of live and necrotic Jurkat cells. B , phase contrast microscopy of live and necrotic N20.1 cells. C , CFSE-labeled LRP1 positive or negative fibroblasts were incubated with live or necrotic CypHer-labeled Jurkat cells for 2 h. After washing, fibroblast-associated CypHer fluorescence was analyzed by flow cytometry. D , results are normalized to the difference of CypHermedianfluorescencebetweenLRP1-positivecellsincubatedwithnecroticcellsanduntreatedLRP1-positivecells(arepresentativeoftwoindependent experimentsis shown; ****, p < 0.0001). E , BV2 cells were incubated with live or necrotic CypHer-labeled N20.1 cells for 30 min. After washing, BV2 were stained with CD11b-Alexa Fluor 488 antibody and BV2-associated CypHer fluorescence was analyzed by flow cytometry. F , results are normalized to the difference of CypHermedianfluorescencebetweenGSTtreatedcellsincubatedwithnecroticcellsanduntreatedBV2cells(arepresentativeofsixindependentexperiments is shown). ***, p < 0.001. ns , not significant.CC-BY · From the PDF

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Metadata

Authors
Fernandez-Castaneda, A., Arandjelovic, S., Stiles, T. L., Schlobach, R. K., Mowen, K. A., Gonias, S. L., & Gaultier, A.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2013-02
Volume
288
Issue
7
Pages
4538-4548
ISSN
0021-9258
DOI
10.1074/jbc.m112.384693
Cited by
55
References
2
Language
en
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CoChat. (2026). Citation check: Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris. https://app.cochat.ai/papers/10.1074/jbc.m112.384693
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Fernandez-Castaneda, A., Arandjelovic, S., Stiles, T. L., Schlobach, R. K., Mowen, K. A., Gonias, S. L., & Gaultier, A. (2013). Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m112.384693