Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function

Lee, Jae Jin; Yang, Seung Ok; Park, Jimin; Ferrell, James E.; Shin, Dongkun; Lee, Kong Joo

doi:10.1038/s41598-017-07072-4

Cited by 18 publications

(25 citation statements)

References 33 publications

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“…As an EF-hand Ca 2 + binding protein [14], SCGN was recently shown to play a key role in the regulation of pancreatic insulin release and β-cell survival in both cell and rodent models. Previous studies [9,15] have reported that SCGN promotes insulin release from pancreatic β-cells by interacting with vesicle fusion and trafficking proteins or with the actin cytoskeleton. Lee et al further elucidated that SCGN regulated insulin secretion in pancreatic cells through Ca 2 + -induced structural changes that promoted the dimerization of SCGN.…”

Section: Discussionmentioning

confidence: 99%

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Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

Yang

Zhao

et al. 2019

Exp Clin Endocrinol Diabetes

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Objective Secretagogin, a Ca2+ binding protein, is one of the most abundant proteins in pancreatic β-cells and is critical for maintaining the structural integrity and signaling competence of β-cells. This study seeks to assess the concentrations of plasma secretagogin in participants with prediabetes (pre-DM) and newly diagnosed type 2 diabetes (T2DM) and to explore its relationship to parameters of glucose and lipid metabolism, first-phase insulin secretion, insulin resistance and pancreatic β-cell function. Materials and Methods A total of 126 eligible subjects were divided into three groups: a normal glucose tolerance (NGT, n=45), a pre-DM (n=30), and a T2DM (n=51) group. An intravenous glucose tolerance test (IVGTT) was performed, and clinical and biochemical parameters were measured for all subjects. Results Plasma secretagogin levels were significantly higher in both pre-DM and T2DM patients compared with NGT subjects and were highest in the T2DM group. Correlation analysis showed that plasma secretagogin levels were positively correlated with fasting plasma glucose, postchallenge plasma glucose (2hPG), HbA1c and body mass index (BMI) but were not correlated with waist-hip ratio, blood pressure, lipid profiles, fasting serum insulin, homeostasis model assessment for insulin resistance, homeostasis model assessment for β-cell function and first-phase insulin secretion indicators. Multiple logistic regression analysis revealed that 2hPG and BMI were independent predictors for elevation of plasma secretagogin concentrations. Conclusions Increased circulating secretagogin might be a molecular predictor for early diagnosis of diabetes. Further studies are needed to confirm this finding and explore the role of secretagogin in obesity.

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Section: Discussionmentioning

confidence: 99%

“…Further studies are needed to elucidate this correlation, as circulating SCGN was thought to be released from islets. Some studies also assessed SCGN expression in pancreatic tissue [15,16]. However, their findings have been conflicting.…”

Section: Discussionmentioning

confidence: 99%

Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

Yang

Zhao

et al. 2019

Exp Clin Endocrinol Diabetes

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“…There have been many efforts to characterize protein structures that have the key to elucidating the complex protein function and dynamics. Recently, protein structural changes by oxidation of peroxiredoxin 2 23 , by calcium binding in EF-hands of secretagogin 24 , and by chemical binding to Nm23-H1 25 and by drug binding to PPARγ 26 have all been well characterized by employing HDX-MS. HDX-MS is a one of the hottest techniques, which costs less effort and money, and at the same time, it has less limitation compared to other methods such as NMR or X-ray crystallography as described previously 27 . With the growing data size and the technology, a fully automated method is essential for high throughput analysis.…”

Section: Discussionmentioning

confidence: 99%

deMix: Decoding Deuterated Distributions from Heterogeneous Protein States via HDX-MS

Lee

Joo

et al. 2019

Sci Rep

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Characterization of protein structural changes in response to protein modifications, ligand or chemical binding, or protein-protein interactions is essential for understanding protein function and its regulation. Amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry (MS) is one of the most favorable tools for characterizing the protein dynamics and changes of protein conformation. However, currently the analysis of HDX-MS data is not up to its full power as it still requires manual validation by mass spectrometry experts. Especially, with the advent of high throughput technologies, the data size grows everyday and an automated tool is essential for the analysis. Here, we introduce a fully automated software, referred to as ‘deMix’, for the HDX-MS data analysis. deMix deals directly with the deuterated isotopic distributions, but not considering their centroid masses and is designed to be robust over random noises. In addition, unlike the existing approaches that can only determine a single state from an isotopic distribution, deMix can also detect a bimodal deuterated distribution, arising from EX1 behavior or heterogeneous peptides in conformational isomer proteins. Furthermore, deMix comes with visualization software to facilitate validation and representation of the analysis results.

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“…Since a significant decrease in insulin secretion and a marked increase in the insulin content were observed in cholesterol-treated MIN6 cells after GSIS, changes in the expression of Scgn, a key regulator of insulin secretion that was recently identified were subsequently detected (12,13,23,24) and observed a dramatic decrease in response to the cholesterol treatment. A bioinformatics analysis was next conducted to predict interactions between miR-24 and Scgn .…”

Section: Discussionmentioning

confidence: 99%

A microRNA‑24‑to‑secretagogin regulatory pathway mediates cholesterol‑induced inhibition of insulin secretion

Yang

Zhang

et al. 2019

Int J Mol Med

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Hypercholesterolemia is a key factor leading to β-cell dysfunction, but its underlying mechanisms remain unclear. Secretagogin (Scgn), a Ca 2+ sensor protein that is expressed at high levels in the islets, has been shown to play a key role in regulating insulin secretion through effects on the soluble N-ethylmaleimide-sensitive factor attachment receptor protein complexes. However, further studies are required to determine whether Scgn plays a role in hypercholesterolemia-associated β-cell dysfunction. The present study investigated the involvement of a microRNA-24 (miR-24)-to-Scgn regulatory pathway in cholesterol-induced β-cell dysfunction. In the present study, MIN6 cells were treated with increasing concentrations of cholesterol and then, the cellular functions and changes in the miR-24-to-Scgn signal pathway were observed. Excessive uptake of cholesterol in MIN6 cells increased the expression of miR-24, resulting in a reduction in Sp1 expression by directly targeting its 3′ untranslated region. As a transcriptional activator of Scgn , downregulation of Sp1 decreased Scgn levels and subsequently decreased the phosphorylation of focal adhesion kinase and paxillin, which is regulated by Scgn. Therefore, the focal adhesions in insulin granules were impaired and insulin exocytosis was reduced. The present study concluded that a miR-24-to-Scgn pathway participates in the mechanism regulating cholesterol accumulation-induced β-cell dysfunction.

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Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function

Cited by 18 publications

References 33 publications

Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

Plasma Secretagogin is Increased in Individuals with Glucose Dysregulation

deMix: Decoding Deuterated Distributions from Heterogeneous Protein States via HDX-MS

A microRNA‑24‑to‑secretagogin regulatory pathway mediates cholesterol‑induced inhibition of insulin secretion

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