A role for the C-terminus of calcitonin in aggregation and gel formation: A comparative study of C-terminal fragments of human and salmon calcitonin

Calcitonin is used in therapy for osteoporosis and Paget's disease. In vitro, human calcitonin forms thick gels which limits its usefulness as a therapeutic, and consequently salmon calcitonin which is less prone to aggregate is commonly used instead. In order to probe the role of the C-terminal region of the molecule in association and gel formation we have prepared a set of three peptides corresponding to the C-terminal regions of salmon calcitonin, human calcitonin and a mutant of human calcitonin in which Pro-23 is substituted with Ala. The peptides are largely disordered in their monomeric state as judged by CD and FTIR. All three peptides aggregate and form gels. Both human peptides form a gel much faster than the salmon peptide and the proline to alanine mutant forms a gel faster than the wildtype human peptide. Gel formation by all three peptides is slower than for intact human calcitonin. CD indicates a difference in conformation for the human fragment but not for the salmon fragment between the monomeric state and the gel state. FTIR experiments suggest the presence of beta-structure in the gel derived from the human peptide but not in the gel derived from the salmon peptide. These results show that there are clear differences in the association properties of the peptides and point to a potential role for the C-terminal region of calcitonin in controlling aggregation/gel formation. (C) 1998 Academic Press.