Abstract
Sorcin is an essential penta-EF hand calcium binding protein, able to confer the multi-drug resistance phenotype to drug-sensitive cancer cells and to reduce Endoplasmic Reticulum stress and cell death. Sorcin silencing blocks cell cycle progression in mitosis and induces cell death by triggering apoptosis. Sorcin participates in the modulation of calcium homeostasis and in calcium-dependent cell signalling in normal and cancer cells. The molecular basis of Sorcin action is yet unknown. The X-ray structures of Sorcin in the apo (apoSor) and in calcium bound form (CaSor) reveal the structural basis of Sorcin action: calcium binding to the EF1-3 hands promotes a large conformational change, involving a movement of the long D-helix joining the EF1-EF2 sub-domain to EF3 and the opening of EF1. This movement promotes the exposure of a hydrophobic pocket, which can accommodate in CaSor the portion of its N-terminal domain displaying the consensus binding motif identified by phage display experiments. This domain inhibits the interaction of sorcin with PDCD6, a protein that carries the Sorcin consensus motif, co-localizes with Sorcin in the perinuclear region of the cell and in the midbody and is involved in the onset of apoptosis.
Highlights
(ER) and cell membranes during interphase, while during mitosis, Sorcin concentrates in the cleavage furrow and midbody
Sorcin undergoes large conformational changes, presumably involving exposure of hydrophobic surfaces, that allows it to interact with calcium channels, pumps and exchangers like ryanodine receptors (RyRs), sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA), L-type voltage-dependent calcium channels and Na+-Ca2+ exchangers (NCX), and to regulate them[14,15,16,17,23,24]
Our study shed new light on the molecular basis of Sorcin activation, i.e. the structural changes induced by calcium binding in Sorcin, and on Sorcin mechanism of action, i.e. the interaction of Sorcin with its molecular partners, which leads to regulation of cytokinesis, to protection from apoptosis and to the establishment of MDR phenotype
Summary
(ER) and cell membranes during interphase, while during mitosis, Sorcin concentrates in the cleavage furrow (late telophase) and midbody (cytokinesis). Upon calcium binding Sorcin undergoes a large conformational change that allows it to bind and regulate a series of target proteins in a calcium-dependent fashion[32,33,34]. The structural basis of its activation and of its ability to establish calcium-dependent interactions with targets is unclear. Our study shed new light on the molecular basis of Sorcin activation, i.e. the structural changes induced by calcium binding in Sorcin, and on Sorcin mechanism of action, i.e. the interaction of Sorcin with its molecular partners, which leads to regulation of cytokinesis, to protection from apoptosis and to the establishment of MDR phenotype
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