title: Insulin solubility transitions by pH-dependent interactions with proinsulin C-peptide.
abstract: Proinsulin processing into insulin and C-peptide in the secretory granules of the pancreatic β-cells occurs under mildly acidic conditions and at high peptide concentrations (> 10 mm). Mature insulin has reduced solubility and a propensity to adopt an amyloid-like structure, but is physiologically released as a mixture of a zinc-containing core and a zinc-free, C-peptide-rich fluid phase. C-peptide is known to function in the insulin secretion, but its exact mode of interaction is not established. We now demonstrate that C-peptide in sub-stoichiometric amount versus insulin coprecipitates with insulin at the pH found in secretory vesicles. Precipitation is reversible and the precipitate is dissolved by elevation of the pH. This effect was found to be dependent on relatively conserved glutamate residues in the otherwise poorly conserved C-peptide. Together, the data show that C-peptide has the ability to influence insulin solubility. The physiological pH changes between insulin processing and release sites may therefore affect the quaternary structure of insulin, as well as the phase transitions during insulin sorting and secretion.
  Insulin and C-peptide bind by molecular sieving (View Interaction: 1, 2) C-peptide and Insulin bind by dynamic light scattering (View Interaction: 1, 2) C-peptide and Insulin bind by fluorescence technology (View Interaction: 1, 2, 3, 4).
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Landreh
authors.forename: Gunvor
authors.initials: G
authors.lastname: Alvelius
authors.forename: Hanna
authors.initials: H
authors.lastname: Willander
authors.forename: Jan-Bernd
authors.initials: JB
authors.lastname: Stukenborg
authors.forename: Olle
authors.initials: O
authors.lastname: Söder
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.forename: Hans
authors.initials: H
authors.lastname: Jörnvall
mesh_terms: D002096:C-Peptide / Q000737:chemistry* / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000737:chemistry*; D012995:Solubility
chemical_list: D002096:C-Peptide; D007328:Insulin