Oligomerization and insulin interactions of proinsulin C-peptide: Threefold relationships to properties of insulin

Jörnvall, Hans; Lindahl, Emma; Astorga‐Wells, Juan; Lind, John; Holmlund, Anna; Melles, Ermias; Alvélius, Gunvor; Nerelius, Charlotte; Mäler, Lena; Johansson, Jan

doi:10.1016/j.bbrc.2009.12.125

Cited by 29 publications

(31 citation statements)

References 31 publications

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“…Although earlier studies have demonstrated that interactions with lipid vesicle bilayers do not result in any membrane-induced structure conversion in C-peptide [12], local variations in environment, including pH, may cause C-peptide to associate with lipids, as demonstrated here, which may affect the aggregation state of the peptide, and the equilibrium between a dominating population of monomeric peptides and a very small population of oligomers may be shifted [14]. Hence, transient membrane interactions may be of importance in vivo for inducing aggregation without any apparent structure intermediate.…”

Section: Discussionmentioning

confidence: 81%

“…Further, residues Q9-L12, residues G15-A18 and residues Q22-A25 were all shown to have structural preferences in the NMR-derived ensemble average [13]. It has recently been demonstrated that C-peptide also has the ability, under certain conditions, such as low pH, to form β -sheet structure, resembling amyloid structures [14, 15]. The peptide forms predominantly low-order oligomers [14], but very low concentrations of amyloid-like structures may also form [15].…”

Section: Introductionmentioning

confidence: 99%

“…It has recently been demonstrated that C-peptide also has the ability, under certain conditions, such as low pH, to form β -sheet structure, resembling amyloid structures [14, 15]. The peptide forms predominantly low-order oligomers [14], but very low concentrations of amyloid-like structures may also form [15]. The formation of amyloid structure can be enhanced in the presence of subcritical micelle concentration (CMC) amounts of SDS (at low pH), while SDS in amounts above the CMC, on the other hand, promote a more α -helical structure [15].…”

Section: Introductionmentioning

confidence: 99%

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pH-Dependent Interaction between C-Peptide and Phospholipid Bicelles

Unnerståle

Mäler

2012

Journal of Biophysics

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C-peptide is the connecting peptide between the A and B chains of insulin in proinsulin. In this paper, we investigate the interaction between C-peptide and phospholipid bicelles, by circular dichroism and nuclear magnetic resonance spectroscopy, and in particular the pH dependence of this interaction. The results demonstrate that C-peptide is largely unstructured independent of pH, but that a weak structural induction towards a short stretch of β-sheet is induced at low pH, corresponding to the isoelectric point of the peptide. Furthermore, it is demonstrated that C-peptide associates with neutral phospholipid bicelles as well as acidic phospholipid bicelles at this low pH. C-peptide does not undergo a large structural rearrangement as a consequence of lipid interaction, which indicates that the folding and binding are uncoupled. In vivo, local variations in environment, including pH, may cause C-peptide to associate with lipids, which may affect the aggregation state of the peptide.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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pH-Dependent Interaction between C-Peptide and Phospholipid Bicelles

Unnerståle

Mäler

2012

Journal of Biophysics

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“…The oligomeric states of several endogenous peptides have been shown to be of relevance with respect to their physiological function. Recently, it was demonstrated, under a wide variety of conditions, including at different pH levels and concentrations, that a small fraction of C-peptide exists as oligomers, as shown both by MS and gel electrophoresis [13], as well as by surface plasmon resonance [12]. This lead us to exam-ine the structure and physical properties of these states further.…”

mentioning

confidence: 99%

“…Regarding internalization, C-peptide enters into different cells [9][10][11], and into nucleoli, with intracrine effects similar to a growth factor affecting ribosomal RNA synthesis [11]. Finally, it has been demonstrated that, extracellularly, C-peptide is involved in the disaggregation of insulin, increasing insulin bioavailability by monomerization [12,13]. C-peptide itself has been shown to adopt unordered structures in aqueous solutions, although it has some defined structural segments and is not influenced further by the presence of negatively-charged lipid vesicles [7,14,15].…”

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confidence: 99%

Structural features of proinsulin C‐peptide oligomeric and amyloid states

et al. 2010

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The formation and structure of proinsulin C-peptide oligomers has been investigated by PAGE, NMR spectroscopy and dynamic light scattering. The results obtained show that C-peptide forms oligomers of different sizes, and that their formation and size distribution is altered by salt and divalent metal ions, which indicates that the aggregation process is mediated by electrostatic interactions. It is further demonstrated that the size distribution of the C-peptide oligomers, in agreement with previous studies, is altered by insulin, which supports a physiologically relevant interaction between these two peptides. A small fraction of oligomers has previously been suggested to be in equilibrium with a dominant fraction of soluble monomers, and this pattern also is observed in the present study. The addition of modest amounts of sodium dodecyl sulphate at low pH increases the relative amount of oligomers, and this effect was used to investigate the details of both oligomer formation and structure by a combination of biophysical techniques. The structural properties of the SDS-induced oligomers, as obtained by thioflavin T fluorescence, CD spectroscopy and IR spectroscopy, demonstrate that soluble aggregates are predominantly in b-sheet conformation, and that the oligomerization process shows characteristic features of amyloid formation. The formation of large, insoluble, b-sheet amyloid-like structures will alter the equilibrium between monomeric C-peptide and oligomers. This leads to the conclusion that the oligomerization of C-peptide may be relevant also at low concentrations.

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Unraveling the aggregation propensity of human insulin C‐peptide

et al. 2017

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Over the last 20 years, proinsulin C-peptide emerged as an important player in various biological events. Much time and effort has been spent in exploring all functional features of C-peptide and recording its implications in Diabetes mellitus. Only a few studies, though, have addressed C-peptide oligomerization and link this procedure with Diabetes. The aim of our work was to examine the aggregation propensity of C-peptide, utilizing Transmission Electron Microscopy, Congo Red staining, ATR-FTIR, and X-ray fiber diffraction at a 10 mg ml concentration. Our experimental work clearly shows that C-peptide self-assembles into amyloid-like fibrils and therefore, the aggregation propensity of C-peptide is a characteristic novel feature that should be related to physiological and also pathological conditions. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 108: 1-8, 2017.

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Oligomerization and insulin interactions of proinsulin C-peptide: Threefold relationships to properties of insulin

Cited by 29 publications

References 31 publications

pH-Dependent Interaction between C-Peptide and Phospholipid Bicelles

pH-Dependent Interaction between C-Peptide and Phospholipid Bicelles

Structural features of proinsulin C‐peptide oligomeric and amyloid states

Unraveling the aggregation propensity of human insulin C‐peptide

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