High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in Children

Šoić, Dinko; Keser, Toma; Štambuk, Jerko; Kifer, Domagoj; Pociot, Flemming; Lauc, Gordan; Morahan, Grant; Novokmet, Mislav; Gornik, Olga

doi:10.1016/j.mcpro.2022.100407

Cited by 7 publications

(9 citation statements)

References 48 publications

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“…Man9 is an oligomannose glycan, and in plasma, it is thought to come from apolipoprotein B-100 (ApoB-100) [ 40 ]. High-mannose structures, including Man9, have also been reported on the Fab portion of IgG and the C3 complement component, with the latter exclusively featuring oligomannose structures [ 41 ]. The presence of oligomannose glycans on vascular endothelial cells has been associated with inflammation, and plays a role in leukocyte trafficking [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

et al. 2023

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Atrial fibrillation is a disease with a complex pathophysiology, whose occurrence and persistence are caused not only by aberrant electrical signaling in the heart, but by the development of a susceptible heart substrate. These changes, such as the accumulation of adipose tissue and interstitial fibrosis, are characterized by the presence of inflammation. N-glycans have shown great promise as biomarkers in different diseases, specifically those involving inflammatory changes. To assess the changes in the N-glycosylation of the plasma proteins and IgG in atrial fibrillation, we analyzed the N-glycosylation of 172 patients with atrial fibrillation, before and six months after a pulmonary vein isolation procedure, with 54 cardiovascularly healthy controls. An analysis was performed using ultra-high-performance liquid chromatography. We found one oligomannose N-glycan structure from the plasma N-glycome and six IgG N-glycans, mainly revolving around the presence of bisecting N-acetylglucosamine, that were significantly different between the case and control groups. In addition, four plasma N-glycans, mostly oligomannose structures and a derived trait that was related to them, were found to be different in the patients who experienced an atrial fibrillation recurrence during the six-month follow-up. IgG N-glycosylation was extensively associated with the CHA2DS2-VASc score, confirming its previously reported associations with the conditions that make up the score. This is the first study looking at the N-glycosylation patterns in atrial fibrillation and warrants further investigation into the prospect of glycans as biomarkers for atrial fibrillation.

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Section: Discussionmentioning

confidence: 99%

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

et al. 2023

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“…The truncated data (0.34 nm -1 < s < 3.0 nm -1 ) suggested a molecular weight credibility interval of [177;221] kDa using the 30 remaining points with smallest s , and an R max of 15.1 nm was reached from the distance distribution function. A model was fitted to the truncated data using CORAL 62 by fixing the C3* model from cryo-EM and allowing placement of MG3, ANA and high-mannose glycosylations on Ans85 and Asn939 64 . The C1 atom of the Asn-linked NAG residues were restrained to be 6 Å from the Cα atom of the connected asparagine.…”

Section: Methodsmentioning

confidence: 99%

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring

Gadeberg,

Jørgensen,

Olesen

et al. 2024

Preprint

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The C3 protein is the central molecule within the complement system and undergoes pattern-recognition-dependent proteolytic activation to C3b in the presence of pathogens and damage-associated patterns. Spontaneous pattern-independent activation of C3 occurs via hydrolysis, resulting in C3(H2O). However, the structural details of C3 hydrolysis remain elusive. Here, we show that the conformation of the C3(H2O) analog, C3MA, in which the C3 thioester is broken by aminolysis is indistinguishable from C3b except for the 77-residue anaphylatoxin (ANA) domain. In contrast, the reaction intermediate C3* formed during C3 adopts a dynamic conformation dramatically different from both C3 and C3MA/C3b. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG-ring through which the ANA domain translocates. In support of this mechanism, C3MA formation is inhibited by an MG3/MG4-interface-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 where an exceptional conformational change allows the translocation of an entire domain through a large dynamic opening. These results form the basis for elucidation of the in vivo contribution of C3 hydrolysis to complement activation and offer a rational approach for modulation of C3(H2O) with the potential for preventing complement activation caused by intravascular hemolysis and surface contacts.

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“…Changes in N-glycome profiles have been described in different diseases including type 1 diabetes and are being considered as biomarkers of ongoing pathological conditions ( 7 – 9 ). Our recent study revealed total plasma N-glycome changes in children with early onset type 1 diabetes, and one of the observed alterations was in the abundance of high-mannose N-glycans ( 10 ). Recent studies investigated serum N-glycosylation changes in adult type 1 diabetes patients with kidney disease and demonstrated that N-glycan profile of both total serum proteins and of IgG is altered.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the continual association of high-mannose glycans and T1D, and the fact that human complement component C3 is a protein occupied with these structures, our team recently studied C3 N-glycome in children and adolescents newly diagnosed with type 1 diabetes and found significant differences from their healthy siblings ( 10 ). C3 is central and most abundant protein of the complement system, a key system for immune surveillance with significant role in the pathogenesis of many diseases, including diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…Our study on young onset type 1 diabetes population was the first study of C3 N-glycosylation changes in any disease, and the results confirmed the relevance of C3 N-glycome analysis. Using our previously developed high-throughput glycoproteomic workflow for a site-specific N-glycosylation LC-MS analysis of human C3 ( 10 ), here we aimed to explore whether C3 N-glycan changes accompany T1D complications’ severity and progression. Additionally, since hypertension, smoking, HbA1c and duration of the disease are all considered major risk factors for T1D microvascular complications, we also inspected their effects on C3 N-glycome.…”

Section: Introductionmentioning

confidence: 99%

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Human complement component C3 N-glycome changes in type 1 diabetes complications

et al. 2023

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AimChanges in N-glycosylation have been described in numerous diseases and are being considered as biomarkers of ongoing pathological condition. Previous studies demonstrated the interrelation of N-glycosylation and type 1 diabetes (T1D), particularly linking serum N-glycan changes with complications accompanying the disease. Moreover, the role of complement component C3 in diabetic nephropathy and retinopathy has been implicated, and C3 N-glycome was found to be altered in young T1D patients. Therefore, we investigated associations between C3 N-glycan profiles and albuminuria and retinopathy accompanying T1D, as well as glycosylation connection with other known T1D complication risk factors.Research design and methodsComplement component C3 N-glycosylation profiles have been analyzed from 189 serum samples of T1D patients (median age 46) recruited at a Croatian hospital centre. Using our recently developed high-throughput method, relative abundances of all six of the C3 glycopeptides have been determined. Assessment of C3 N-glycome interconnection with T1D complications, hypertension, smoking status, estimated glomerular filtration rate (eGFR), glycaemic control and duration of the disease was done using linear modelling.ResultsSignificant changes of C3 N-glycome in severe albuminuria accompanying type 1 diabetes were observed, as well as in T1D subjects with hypertension. All except one of the C3 glycopeptides proved to be associated with measured HbA1c levels. One of the glycoforms was shown to be changed in non-proliferative T1D retinopathy. Smoking and eGFR showed no effect on C3 N-glycome. Furthermore, C3 N-glycosylation profile was shown to be independent of disease duration.ConclusionThis study empowered the role of C3 N-glycosylation in T1D, showing value in distinguishing subjects with different diabetic complications. Being independent of the disease duration, these changes may be associated with the disease onset, making C3 N-glycome a potential novel marker of the disease progression and severity.

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High-Throughput Human Complement C3 N-Glycoprofiling Identifies Markers of Early Onset Type 1 Diabetes Mellitus in Children

Cited by 7 publications

References 48 publications

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring

Human complement component C3 N-glycome changes in type 1 diabetes complications

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