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 pro ne to aggregate is commonly used instead. In order to probe the role o f the C-terminal region of the molecule in association and gel formati on we have prepared a set of three peptides corresponding to the C-ter minal regions of salmon calcitonin, human calcitonin and a mutant of h uman calcitonin in which Pro-23 is substituted with Ala. The peptides are largely disordered in their monomeric state as judged by CD and FT IR. All three peptides aggregate and form gels. Both human peptides fo rm a gel much faster than the salmon peptide and the proline to alanin e mutant forms a gel faster than the wildtype human peptide. Gel forma tion 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 st ate. FTIR experiments suggest the presence of beta-structure in the ge l derived from the human peptide but not in the gel derived from the s almon peptide. These results show that there are clear differences in the association properties of the peptides and point to a potential ro le for the C-terminal region of calcitonin in controlling aggregation/ gel formation. (C) 1998 Academic Press.