Abstract
Several potentially atherogenic LDL subfractions present low affinity for the LDL receptor, which result in impaired plasma clearance. Electronegative LDL [LDL(-)] is one of these minor subfractions and the molecular basis for its reduced receptor affinity is not well understood. In the present study, high-resolution 2D-NMR spectroscopy has been employed to characterize the surface-exposed lysine residues of the apolipoprotein (apo)B-100 protein in both LDL(-) and LDL(+) subfractions. LDL(+) showed two populations of lysine residues, similar to those previously described in total LDL. "Normal" Lys have a pk(a) of 10.4 whereas "active" Lys have a pk(a) of 8.8 and have been suggested to be involved in receptor binding. In contrast to LDL(+), the LDL(-) subfraction presented a third type of Lys, named as "intermediate" Lys, with a different microenvironment and higher basicity (pk(a) 10.7). These intermediate Lys cannot be reliably identified by 1D-NMR. Because the abundance of normal Lys is similar in LDL(+) and LDL(-), the intermediate Lys in the apoB-100 molecule of LDL(-) should come from a group of active Lys in LDL(+) particles that have a less basic microenvironment in the LDL(-) particle. These differences between LDL(+) and LDL(-) are indicative of a distinct conformation of apoB-100 that could be related to loss of affinity of LDL(-) for the LDL receptor.
Highlights
Is one of these minor subfractions and the molecular basis for its reduced receptor affinity is not well understood
Lys residues in apoB-100 are involved in LDL recognition by its receptor [17] and their chemical modification by different mechanisms abolishes their binding
The lower pka indicated a more basic microenvironment within the apoB-100 molecule. This group was termed active Lys, the other being normal Lys, and was suggested to be involved in LDLr recognition [11, 12]. These authors demonstrated that plasma LDL subspecies with low affinity toward the LDL receptor, such as small, dense, or large, buoyant LDL subfractions [21], have altered ionization of basic amino acids with a reduced proportion of active Lys [13]
Summary
Is one of these minor subfractions and the molecular basis for its reduced receptor affinity is not well understood. 2D-NMR reveals different populations of exposed lysine residues in the apoB-100 protein of electronegative and electropositive fractions of LDL particles. LDL(–) differs from LDL(+) in its higher susceptibility to aggregation [7], its capability to form lipid clusters [8], its secondary structure content of apoB-100 [9], and in the propensity of apoB-100 to form amyloid-like structures [10]. Another atherogenic property of LDL(–) is its low affinity for the LDL receptor (LDLr) [6].
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