Abstract
Sorcin is a penta-EF hand calcium binding protein, which participates in the regulation of calcium homeostasis in cells. Sorcin regulates calcium channels and exchangers located at the plasma membrane and at the endo/sarcoplasmic reticulum (ER/SR), and allows high levels of calcium in the ER to be maintained, preventing ER stress and possibly, the unfolded protein response. Sorcin is highly expressed in the heart and in the brain, and overexpressed in many cancer cells. Sorcin gene is in the same amplicon as other genes involved in the resistance to chemotherapeutics in cancer cells (multi-drug resistance, MDR) such as ABCB4 and ABCB1; its overexpression results in increased drug resistance to a number of chemotherapeutic agents, and inhibition of sorcin expression by sorcin-targeting RNA interference leads to reversal of drug resistance. Sorcin is increasingly considered a useful marker of MDR and may represent a therapeutic target for reversing tumor multidrug resistance.
Highlights
Sorcin and the Other Penta-EF Hand ProteinsThe EF-hand is a common helix-loop-helix structural motif used by proteins to bind calcium [1].Most proteins are endowed with an even number of EF-hands, which are usually structurally and functionally paired
Apart from its direct ability to interact with Ryanodine receptors (RyRs) and to inhibit it, maintaining calcium load in endoplasmic reticulum (ER) and possibly decreasing the unfolded protein response in the brain, sorcin directly interacts in a calcium-dependent fashion with alpha-synuclein (AS) and presenilin 2 (PS2), two proteins involved in the pathogenesis of Parkinson disease (PD) and Alzheimer's disease (AD), respectively, in vitro, in cultured cells and in human brain [58,59]
The levels of expression of sorcin is much lower than that of calmodulin, sorcin is differentially expressed in cancers and other pathological conditions and is able to interact with a series of crucial targets and to regulate them
Summary
The EF-hand is a common helix-loop-helix structural motif used by proteins to bind calcium [1]. Soluble resistance-related calcium binding protein (sorcin) is a calcium binding protein belonging to the penta-EF hand (PEF) family, which includes sorcin, calpains, PDCD6. The members of the PEF protein family participate in different cellular processes, but share several common features: (i) all these proteins have two domains, a flexible and hydrophobic Gly/Pro-rich. N-terminal domain, and a C-terminal calcium binding domain containing five EF-hand motifs; (ii) the PEF proteins are dimers, and monomer-monomer association occurs through the unpaired C-terminal. The N-terminal domain is often short and flexible, in the case of the large subunit of calpains, it can be rather complex, and includes a protease domain. The C-terminal, calcium-binding domain, is rather well conserved among the PEF proteins (Figure 1). Glu, Trp, Trp105, Phe112 and Glu124 are indicated in bold and blue
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