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Predicate | Object |
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rdf:type | |
lifeskim:mentions |
umls-concept:C0051300,
umls-concept:C0127400,
umls-concept:C0147139,
umls-concept:C0178539,
umls-concept:C0243125,
umls-concept:C0699900,
umls-concept:C1148608,
umls-concept:C1415483,
umls-concept:C1510827,
umls-concept:C1514562,
umls-concept:C1704675,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221
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pubmed:issue |
10
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pubmed:dateCreated |
1997-4-14
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pubmed:abstractText |
Thrombospondin-1 (TSP-1) is a large modular trimeric protein that has been proposed to play a diverse role in biological processes. Newly synthesized TSP-1 either is incorporated into the matrix or binds to the cell surface where it is rapidly internalized and degraded. TSP-1 catabolism is mediated by the low density lipoprotein receptor-related protein (LRP), a large endocytic receptor that is a member of the low density lipoprotein receptor family. Using adenovirus-mediated gene transfer experiments, we demonstrate that the very low density lipoprotein receptor can also bind and internalize TSP-1. An objective of the current investigation was to identify the portion of TSP-1 that binds to these endocytic receptors. The current studies found that the amino-terminal heparin binding domain (HBD, residues 1-214) of mouse TSP-1, when prepared as a fusion protein with glutathione S-transferase (GST), bound to purified LRP with an apparent KD ranging from 10 to 25 nM. Recombinant HBD (rHBD) purified following proteolytic cleavage of GST-HBD, also bound to purified LRP, but with an apparent KD of 830 nM. The difference in affinity was attributed to the fact that GST-HBD exists in solution as a dimer, whereas rHBD is a monomer. Like TSP-1, 125I-labeled GST-HBD or 125I-labeled rHBD were internalized and degraded by wild type fibroblasts that express LRP, but not by fibroblasts that are genetically deficient in LRP. The catabolism of both 125I-labeled GST-HBD and rHBD in wild type fibroblast was blocked by the 39-kDa receptor-associated protein, an inhibitor of LRP function. GST-HBD and rHBD both completely blocked catabolism of 125I-labeled TSP-1 in a dose-dependent manner, as did antibodies prepared against the HBD. Taken together, these data provide compelling evidence that the amino-terminal domain of TSP-1 binds to LRP and thus the recognition determinants on TSP-1 for both LRP and for cell surface proteoglycans reside within the same TSP-1 domain. Further, high affinity binding of TSP-1 to LRP likely results from the trimeric structure of TSP-1.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Heparin,
http://linkedlifedata.com/resource/pubmed/chemical/Low Density Lipoprotein...,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Immunologic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Thrombospondins,
http://linkedlifedata.com/resource/pubmed/chemical/VLDL receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
7
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pubmed:volume |
272
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6784-91
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:9045712-Animals,
pubmed-meshheading:9045712-Binding Sites,
pubmed-meshheading:9045712-Biological Transport,
pubmed-meshheading:9045712-Endocytosis,
pubmed-meshheading:9045712-Heparin,
pubmed-meshheading:9045712-Humans,
pubmed-meshheading:9045712-Low Density Lipoprotein Receptor-Related Protein-1,
pubmed-meshheading:9045712-Membrane Glycoproteins,
pubmed-meshheading:9045712-Mice,
pubmed-meshheading:9045712-Protein Conformation,
pubmed-meshheading:9045712-Receptors, Immunologic,
pubmed-meshheading:9045712-Receptors, LDL,
pubmed-meshheading:9045712-Structure-Activity Relationship,
pubmed-meshheading:9045712-Thrombospondins
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pubmed:year |
1997
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pubmed:articleTitle |
Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein.
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pubmed:affiliation |
Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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