Neutral Sites for Calcium Ion Binding to Elastin and Collagen: A Charge Neutralization Theory for Calcification and Its Relationship to Atherosclerosis

Abstract

Neutral, uncharged binding sites for calcium ions are proposed for elastin and collagen. The sites utilize, particularly from a conformational viewpoint, the most striking feature of the amino acid composition, that is, the high glycine content. Glycines favor the formation of B-turns and associated conformations that are known, from studies on ion-transporting antibiotics, to interact with cations. By analogy with certain antibiotics, which are uncharged polypeptides and depsipeptides that bind cations by coordination with neutral acyl oxygens, it is proposed that calcium-ion binding also utilizes uncharged coordinating groups, i.e., neutral sites, in the protein matrix. The protein matrix, which becomes positively charged by virtue of the bound calcium ions, attracts neutralizing phosphate and carbonate ions, which then allow further calcium ion binding. The driving force is, therefore, the affinity of calcium ions for the neutral nucleation sites.The charge neutralization theory of calcification suggests a fundamental role of organic anions, for example sulfated mucopolysaccharides, in regulating bone formation and in retardation of atherosclerosis. The proposed mechanism contains elements that tend to unify several theories on the pathogenesis of atherosclerosis.Elastin and collagen, particularly the former, exhibit a high affinity for calcium ions. There is, in fact, substantive argument, for example, that calcification of elastin is the initial process in the onset of the chronic disease arteriosclerosis; and the initiation of calcification is obviously an important process in bone and tooth formation as well as tendon insertion into bone and the emplacement of teeth. The significance of the initiation of calcification was emphasized by Urist (1) in his review of Selye's theory of calciphylaxis (2) when he stated

Characterization of an <i>in vitro</i> Model of Calcification in Retinal Pigmented Epithelial Cells

“…Also, this model most likely allows elucidation of the important sites of these TE reactions by using mutant TE. We have reported that tropoelastin downregulates the induction of calcification via the elastin receptor (manuscript in submission), although the pathway of the inhibitory reaction by TE on calcification presents several candidate reactions such as the activation of signal transduction via the elastin receptor (33) and the binding of calcium by tropoelastin molecule (6,7). Moreover, it has been reported that TE has a variety of biological effects which are mediated by the elastin receptor, chemotactic cell migration, modulation of ion flux, adhesion of cells to elastin fibers, tumor cellmatrix interaction, elastase synthesis and release, free radical production, endothelium and nitric oxide-mediated vasorelaxation, chaperon for elastogenesis, lymphocyte proliferation, apoptotic cell death (34)(35)(36)(37)(38) as well as properties as a major elastic fiber component.…”

“…In addition to these changes, vascular calcification causes physical changes such as decreased elasticity of vessels, which is partly responsible for disorders related to elastic fibers (4). Previous reports have demonstrated that calcium deposition occurs along elastic fibers in vascular calcification (5) and that the properties of elastin include calcium binding activity (6,7). We have already reported that calcium deposition is found predominantly in autoclaving-resistent elastin fractions in rat-calcified models (8).…”

Tropoelastin Inhibits Vascular Calcification via 67-kDa Elastin Binding Protein in Cultured Bovine Aortic Smooth Muscle Cells

“…Previous reports have demonstrated calcium deposition along elastic fibers in vascular calcification (27), and it has been shown that one property of elastin is calcium binding activity (28)(29)(30)(31). We have already reported that calcium deposition can be clearly observed in autoclaving-resistant elastin fractions using an in vivo calcified model (32,33).…”

Bilateral periocular actinic granuloma in a patient with renal failure: a clinicopathologic study

“…It may be a result of production of abnormal elastic fibers, alteration in the extracellular matrix, or degeneration of elastic fibers [36]. This calcification is part of the aging process and is in part responsible for arterosclerotic changes [35].…”