Negatively cooperative binding of high-density lipoprotein to the HDL receptor SR-BI.
Scavenger receptor class B, type I (SR-BI), is a high-density lipoprotein (HDL) receptor, which also binds low-density lipoprotein (LDL), and mediates the cellular selective uptake of cholesteryl esters from lipoproteins. SR-BI also is a coreceptor for hepatitis C virus and a signaling receptor that regulates cell metabolism. Many investigators have reported that lipoproteins bind to SR-BI via a single class of independent (not interacting), high-affinity binding sites (one site model). We have reinvestigated the ligand concentration dependence of (125)I-HDL binding to SR-BI and SR-BI-mediated specific uptake of [(3)H]CE from [(3)H]CE-HDL using an expanded range of ligand concentrations (<1 μg of protein/mL, lower than previously reported). Scatchard and nonlinear least-squares model fitting analyses of the binding and uptake data were both inconsistent with a single class of independent binding sites binding univalent lipoprotein ligands. The data are best fit by models in which SR-BI has either two independent classes of binding sites or one class of sites exhibiting negative cooperativity due to either classic allostery or ensemble effects ("lattice model"). Similar results were observed for LDL. Application of the "infinite dilution" dissociation rate method established that the binding of (125)I-HDL to SR-BI at 4 °C exhibits negative cooperativity. The unexpected complexity of the interactions of lipoproteins with SR-BI should be taken into account when interpreting the results of experiments that explore the mechanism(s) by which SR-BI mediates ligand binding, lipid transport, and cell signaling.
Department of Biology, Massachusetts Institute of Technology, Room 68-483, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Thomas J F
TJ
Nieland
Shangzhe
S
Xu
Marsha
M
Penman
Monty
M
Krieger
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D008078:Cholesterol, LDL / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000737:chemistry* / Q000378:metabolism*
D008078:Cholesterol, LDL; D008024:Ligands; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors
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