Biological activity versus physiological function of proinsulin C-peptide
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Cellular and Molecular Life Sciences
VISIONS AND REFLECTIONS
Biological activity versus physiological function of proinsulin C‑peptide Michael Landreh1 · Hans Jörnvall2 Received: 6 May 2020 / Revised: 7 August 2020 / Accepted: 3 September 2020 © The Author(s) 2020
Abstract Proinsulin C-peptide (C-peptide) has drawn much research attention. Even if the peptide has turned out not to be important in the treatment of diabetes, every phase of C-peptide research has changed our view on insulin and peptide hormone biology. The first phase revealed that peptide hormones can be subject to processing, and that their pro-forms may involve regulatory stages. The second phase revealed the possibility that one prohormone could harbor more than one activity, and that the additional activities should be taken into account in the development of hormone-based therapies. In the third phase, a combined view of the evolutionary patterns in hormone biology allowed an assessment of C-peptide´s role in physiology, and of how biological activities and physiological functions are shaped by evolutionary processes. In addition to this distinction, C-peptide research has produced further advances. For example, C-peptide fragments are successfully administered in immunotherapy of type I diabetes, and plasma C-peptide levels remain a standard for measurement of beta cell activity in patients. Even if the concept of C-peptide as a hormone is presently not supported, some of its bioactivities continue to influence our understanding of evolutionary changes of also other peptides. Keywords Protein aggregation · Bioactive peptides · Protein evolution · Diabetes mellitus
Introduction Proinsulin C-peptide, or C-peptide, for short, constitutes the mid-section of proinsulin that remains after proteolytic removal of insulin and four basic residues. The human form has 31 residues and is secreted into the blood together with insulin. The discovery of proinsulin by Donald F. Steiner in 1967 contributed to the establishment of the concept of prohormones that require processing to adopt their biologically active forms [1, 2]. It also sparked scientific inquiries into the physiological importance of C-peptide. Today, we know of two such established functions. One is to promote correct folding and disulfide pairing of proinsulin (and hence * Hans Jörnvall [email protected]; [email protected] Michael Landreh [email protected] 1
Departments of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum 9C, 171 77 Stockholm, Sweden
Medical Biochemistry and Biophysics, Karolinska Institutet, Biomedicum 9C, 171 77 Stockholm, Sweden
2
insulin) during synthesis [3–5], the other to participate in the complex interactions that promote the secretion of insulin from the pancreas [6]. Additional activities of C-peptide have been sought for since long, and several have been found [7–10], but none has yet been proven to have a true, functional role. Two reasons for searches of additional C-peptide activities have been that (1) C-peptide diffe
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