Elucidation of a Copper Binding Site in Proinsulin C-peptide and Its Implications for Metal-Modulated Activity

Michael J. Stevenson, Samuel E. Janisse, Lizhi Tao, Ryan L. Neil, Quang D. Pham, R. David Britt, Marie C. Heffern

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The connecting peptide (C-peptide) is a hormone with promising health benefits in ameliorating diabetes-related complications, yet mechanisms remain elusive. Emerging studies point to a possible dependence of peptide activity on bioavailable metals, particularly Cu(II) and Zn(II). However, little is known about the chemical nature of the interactions, hindering advances in its therapeutic applications. This work uncovers the Cu(II)-binding site in C-peptide that may be key to understanding its metal-dependent function. A combination of spectroscopic studies reveal that Cu(II) and Zn(II) bind to C-peptide at specific residues in the N-terminal region of the peptide and that Cu(II) is able to displace Zn(II) for C-peptide binding. The data point to a Cu(II)-binding site consisting of 1N3O square-planar coordination that is entropically driven. Furthermore, the entire random coil peptide sequence is needed for specific metal binding as mutations and truncations reshuffle the coordinating residues. These results expand our understanding of how metals influence hormone activity and facilitate the discovery and validation of both new and established paradigms in peptide biology.

Original languageEnglish (US)
Pages (from-to)9339-9349
Number of pages11
JournalInorganic Chemistry
Issue number13
StatePublished - Jul 6 2020

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Inorganic Chemistry


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