Actin–DBP: the perfect structural fit?

Abstract

The multifunctional vitamin D binding protein (DBP) is an actin-sequestering protein present in blood. The crystal structure of the actin-DBP complex was determined at 2.4 A resolution. DBP binds to actin subdomains 1 and 3 and occludes the cleft at the interface between these subdomains. Most remarkably, DBP demonstrates an unusually large actin-binding interface, far exceeding the binding-interface areas reported for other actin-binding proteins such as profilin, DNase I and gelsolin. The fast-growing side of actin monomers is blocked completely through a perfect structural fit with DBP, demonstrating how DBP effectively interferes with actin-filament formation. It establishes DBP as the hitherto best actin-sequestering protein and highlights its key role in suppressing and preventing extracellular actin polymerization.

Investigation of the potential association of vitamin D binding protein with lipoproteins

“…Although DBP and gelsolin are both present in large concentrations in blood, their capacity to scavenge actin may still be overwhelmed during massive cell necrosis. 224,28 Low total and actin-free DBP concentrations have been demonstrated to be prognostic markers in situations of severe organ damage. 4 The influence of the different lipidbound fractions on the actin scavenging function needs to be explored.…”

Proteomics Analysis of Cytokine-induced Dysfunction and Death in Insulin-producing INS-1E Cells

“…Chaperonin subunit (CCT8) and chaperonin subunit (CCT6A), two chaperones of ␤-actin, are involved in molecular chaperoning, in the production and folding of native actin, and in elongation of actin filaments (32). Vitamin D-binding protein (GC) plays a role in the transport of depolymerized actin molecules (33). -P indicates phosphorylation.…”

Proteomic analysis of plasma from Portuguese patients with familial amyotrophic lateral sclerosis

“…The polymerization of actin would then be increased by decreased DBP in plasma, as it is known that the DBP variants are associated with different plasma concentrations of total DBP, being highest in GC1-1, intermediate in GC1-2 and lowest in GC2-2 (29). Furthermore, it is probable that the GC2 isoform, which is predominant in the FALS patients analysed, would have a decreased affinity for actin, as the amino acid variants identified lie within the domains shown to directly interact with actin (26,30). These hypotheses would translate into an increased susceptibility of particular ALS patients to actin-mediated intravascular damage.…”

“…The presence of filamentous actin in the blood may cause vascular obstruction and organ dysfunction (26). In addition, actin can promote clot formation by its ability to aggregate platelets (27).…”