Secretagogin is a Ca2+-dependent stress-responsive chaperone that may also play a role in aggregation-based proteinopathies.

Secretagogin (SCGN) is a three-domain hexa-EF-hand Ca2+-binding protein that plays a regulatory role in the release of several hormones. SCGN is expressed largely in pancreatic ß-cells, certain parts of the brain, and also in neuroendocrine tissues. The expression of SCGN is altered in several diseases, such as diabetes, cancers, and neurodegenerative disorders; however, the precise associations that closely link SCGN expression to such pathophysiologies are not known. In this work, we report that SCGN is an early responder to cellular stress, and SCGN expression is temporally upregulated by oxidative stress and heat shock. We show the overexpression of SCGN efficiently prevents cells from heat shock and oxidative damage. We further demonstrate that in the presence of Ca2+, SCGN efficiently prevents the aggregation of a broad range of model proteins in vitro. Small-angle X-ray scattering (BioSAXS) studies further reveal that Ca2+ induces the conversion of a closed compact apo-SCGN conformation into an open extended holo-SCGN conformation via multistate intermediates, consistent with the augmentation of chaperone activity of SCGN. Furthermore, isothermal titration calorimetry establishes that Ca2+ enables SCGN to bind α-synuclein and insulin, two target proteins of SCGN. Altogether, our data not only demonstrate that SCGN is a Ca2+-dependent generic molecular chaperone involved in protein homeostasis with broad substrate specificity but also elucidate the origin of its altered expression in several cancers. We describe a plausible mechanism of how perturbations in Ca2+ homeostasis and/or deregulated SCGN expression would hasten the process of protein misfolding, which is a feature of many aggregation-based proteinopathies.

Secretagogin Binding Prevents α-Synuclein Fibrillation.

Secretagogin (SCGN) is a secreted calcium sensor that has emerged as a potential multifunctional protein of neuroendocrine cells. A significantly reduced level of expression of SCGN has been reported in the hippocampus of a mouse model of Alzheimer's disease (AD) and in Parkinson's patients, although the biochemical implications and mechanistic underpinnings of the altered SCGN expression in neurodegenerative diseases remain unknown. We have pursued the interaction of SCGN with α-synuclein that we discovered in impartial pull-down analyses to decode the SCGN interactome. SCGN physically binds α-synuclein and rescues it from detrimental fibrillation. Correspondingly, it is observed that a significant reduction in the cytotoxicity of α-synuclein fibrils is caused by SCGN. We map these antifibrillar attributes to the central region and C-terminal domain of SCGN, while the N-terminal domain is not essential for this activity. On the basis of these results, a broader neuroprotective function of SCGN by proficient chaperone action is proposed. An intriguing correlation of this interaction with a reduced level of expression of SCGN in neurodegenerative diseases shall inspire further studies of the physiological role of SCGN in precluding pathological protein aggregation.

Polymer modified magnetic-luminescent nanocomposites for combined optical imaging and magnetic fluid hyperthermia in cancer therapy: analysis of Mn2+ doping for enhanced heating effect, hemocompatibility and biocompatibility.

Magnetic MnxFe3-xO4 nanoparticles and polymer coated magnetic-luminescent MnxFe3-xO4@(Y,Dy/Eu)VO4 nanocomposites were prepared to study their comparative heat generation efficiency and biocompatibilities. Cubic crystalline phases were obtained for the nanoparticles and cubic-tetragonal biphasic phases were observed for the nanocomposites. The successful doping of Mn2+ was also confirmed by inductively coupled plasma optical emission spectroscopy. The compositions and the surface modification chemistry were confirmed by infrared spectroscopy. The formation of near-spherical and cubic/cuboid nanoparticles was observed from electron microscopy. Comparative analysis of induction heating efficiencies and magnetization values of the synthesized materials was performed for the samples. The samples showed an efficient heating effect under the influence of alternating magnetic field strengths - 3.05 × 106 kA m-1 s-1 and 4.58 × 106 kA m-1 s-1. A higher Mn2+ content was found to possess higher magnetization and perform better in heat generation. The nanocomposites give brilliant color emission on excitation using ultraviolet wavelengths - 300 and 315 nm. Their hydrodynamic radii and zeta potential values indicate good stability of the dispersions. Hemocompatibility studies were carried out to ascertain the effect on red blood cells. The materials were also found to exhibit excellent biocompatibility towards HeLa cell lines. This article will provide a new insight into the use of MnxFe3-xO4 based nanocomposites for magnetic fluid hyperthermia in cancer therapy.

Secretagogin Regulates Insulin Signaling by Direct Insulin Binding.

Secretagogin (SCGN) is a ß-cell enriched, secretory/cytosolic Ca2+-binding protein with unknown secretory regulation and functions. Recent findings suggest that SCGN deficiency correlates with compromised insulin response and diabetes. However, the (patho)physiological SCGN-insulin nexus remains unexplored. We here report that SCGN is an insulin-interacting protein. The protein-protein interaction between SCGN and insulin regulates insulin stability and increases insulin potency in vitro and in vivo. Mutagenesis studies suggest an indispensable role for N-terminal domain of SCGN in modulating insulin stability and function. SCGN supplementation in diabetogenic-diet-fed mice preserves physiological insulin responsiveness while relieving obesity and cardiovascular risk. SCGN-insulin interaction mediated alleviation of hyperinsulinemia by increased insulin internalization, which translates to reduced body fat and hepatic lipid accumulation, emerges as a plausible mechanism for the preservation of insulin responsiveness. These findings establish SCGN as a functional insulin-binding protein (InsBP) with therapeutic potential against diabetes.