The effect of glycosylation on the transferrin structure: A molecular dynamic simulation analysis

Ghanbari, Zahra; Housaindokht, Mohammad Reza; Bozorgmehr, Mohammad Reza; Izadyar, Mohammad

doi:10.1016/j.jtbi.2016.05.024

Cited by 17 publications

(13 citation statements)

References 87 publications

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“…9 The molecular dynamics model showed that the reduction in the iron-binding capacity of glycated apo-Tf might be related to the stereochemical effect caused by the glycation of the lysine residue in the molecule, which interfered with the conformational change required for its binding to the metal. 63 As the glycated sites of holo-Tf were distal from the iron-binding site, the abnormal iron release caused by glycation could be related to the cumulative effect of the instability of the overall structure due to the destruction of the hydrogen bond in the Tf molecule and the electrostatic interaction. 10 The specificity of Tf glycated modification sites under high glucose conditions might affect their normal structure and function.…”

Section: Molecular Mechanisms Of Non-enzymatic Glycated Tf In Diabetes and Diabetic Complicationsmentioning

confidence: 99%

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Ma¹,

Cai²,

Wang³

et al. 2021

DMSO

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Diabetes is a metabolic disease characterized by high blood sugar. Its complications may damage multiple organs, such as eyes, kidneys, heart, blood vessels, and nerves, severely threatening human health. Transferrin (Tf) is a major iron transport protein in the body. Recent studies have shown that the degree of non-enzymatic glycated modification of Tf is increased in diabetic patients, and glycated Tf is closely related to the occurrence and development of diabetes and diabetic complications. However, the molecular mechanisms underlying this glycated modification in diabetes and diabetic complications are still unclear. It is speculated that the mechanism may be that glycated modification reduces the binding ability of Tf and its receptor TfR, followed by excessive iron accumulation in the body. Iron overload in the body may further lead to the death of pancreatic beta cells and insulin resistance by increasing oxidative stress, inducing iron death, interfering with the insulin signaling pathway, and causing autophagy deficiency. In addition, non-enzymatic glycation affects the binding of Tf with chromium and reduces the ability of Tf to transport chromium into tissues, resulting in a decrease in the levels of chromium in tissues and ultimately affecting the sensitivity of tissues to insulin. In diabetic patients, the concentrations of glycated Tf in serum were significantly correlated with those of fructosamine.Tf has a shorter half-life, and not affected by anemia or hypoalbuminemia and less negative charge under physiological conditions, while glycated modification could not change the isoelectric point of Tf, which easily passes through the negatively charged basement membrane of the glomerulus. Therefore, compared to glucosamine, HbA1C, etc., glycated Tf may be a future biomarker for evaluating short-term glycemic control and early renal damage in diabetic patients.

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Section: Molecular Mechanisms Of Non-enzymatic Glycated Tf In Diabetes and Diabetic Complicationsmentioning

confidence: 99%

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Ma¹,

Cai²,

Wang³

et al. 2021

DMSO

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“…Ghanbari et al reported that the glycans on the C-lobe of OTF might affect the layout of the iron binding site residue and subsequently affect the transferrin function. 36 As shown in Figure 5, most of the N-glycosites were concentrated on the transferrin domain (PF00405), which contained active sites showing ferric iron binding activity. Consequently, it could be suggested that these concentrated N-glycans may influence the dynamics of OTF structures and subsequently affect the antibacterial activity.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…According to the high sequence identity between the DEW and CEW OTFs, the higher amount of N-glycosites in DEW OTF might be the main reason for its variation in antimicrobial activity. Ghanbari et al reported that the glycans on the C-lobe of OTF might affect the layout of the iron binding site residue and subsequently affect the transferrin function . As shown in Figure , most of the N-glycosites were concentrated on the transferrin domain (PF00405), which contained active sites showing ferric iron binding activity.…”

Section: Resultsmentioning

confidence: 99%

Identification of the Duck Egg White N-Glycoproteome and Insight into the Course of Biological Evolution

Meng

Qiu

Geng

et al. 2019

J. Agric. Food Chem.

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Protein glycosylation is a ubiquitous posttranslational modification that modulates protein properties, thereby influencing bioactivities within a system. Duck egg white (DEW) proteins exhibit diverse biological properties compared with their chicken egg white (CEW) counterparts, which might be related to glycosylation. N-Glycoproteome analysis of DEW was conducted, and a total of 231 N-glycosites from 68 N-glycoproteins were identified. Gene ontology analysis was used to elucidate the biofunctions of DEW N-glycoproteins and compare them with those of CEW, which showed that the differences mostly involved molecular functions and biological processes. The biological functions of DEW N-glycoproteins were illuminated through bioinformatics analysis and comparison with CEW orthologues, which showed different allergenicities and antibacterial abilities. These divergences might be initiated by specific alterations in glycosylation, which can enhance the proteolysis resistance and protein steric hindrance. These results provide new insights for discovering the effects of N-glycosylation on biofunctions during the divergence of homologous proteins.

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“…13 Indeed, molecular dynamic simulation results have tentatively revealed the role of N-glycosylation at the C-lobe in regulating the 3D structure of TF as well as the impact of sialylation on N-glycan flexibility and conformation. 14,15 As illustrated, Scheme 1 represents the widely acknowledged cartoon illustrations 10,16 of TF-assisted iron delivery into cells (note: the incorporation of amyloid beta (Aβ) has not been previously validated). Key steps involve the TF receptormediated endocytosis and internalization of iron-loaded TF, followed by iron redox, circulation, storage, and TF recycle.…”

Section: ■ Introductionmentioning

confidence: 99%

Native Ion Mobility–Mass Spectrometry-Enabled Fast Structural Interrogation of Labile Protein Surface Modifications at the Intact Protein Level

Phetsanthad

et al. 2022

Anal. Chem.

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Protein sialylation has been closely linked to many diseases including Alzheimer’s disease (AD). It is also broadly implicated in therapeutics operating in a pattern-dependent (e.g., Neu5Ac vs Neu5Gc) manner. However, how the sialylation pattern affects the AD-associated, transferrin-assisted iron/Aβ cellular uptake process remains largely ill-defined. Herein, we report the use of native ion mobility–mass spectrometry (IM–MS)-based fast structural probing methodology, enabling well-controlled, synergistic, and in situ manipulation of mature glycoproteins and attached sialic acids. IM–MS-centered experiments enable the combinatorial interrogation of sialylation effects on Aβ cytotoxicity and the chemical, conformational, and topological stabilities of transferrin. Cell viability experiments suggest that Neu5Gc replacement enhances the transferrin-assisted, iron loading-associated Aβ cytotoxicity. Native gel electrophoresis and IM–MS reveal that sialylation stabilizes transferrin conformation but inhibits its dimerization. Collectively, IM–MS is adapted to capture key sialylation intermediates involved in fine-tuning AD-associated glycoprotein structural microheterogeneity. Our results provide the molecular basis for the importance of sustaining moderate TF sialylation levels, especially Neu5Ac, in promoting iron cellular transportation and rescuing iron-enhanced Aβ cytotoxicity.

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The effect of glycosylation on the transferrin structure: A molecular dynamic simulation analysis

Cited by 17 publications

References 87 publications

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Identification of the Duck Egg White N-Glycoproteome and Insight into the Course of Biological Evolution

Native Ion Mobility–Mass Spectrometry-Enabled Fast Structural Interrogation of Labile Protein Surface Modifications at the Intact Protein Level

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