2JXZ
Solution Conformation of A Non-Amyloidogenic Analogue of Human Calcitonin in Sodium Dodecyl Sulfate Micelles
Summary for 2JXZ
| Entry DOI | 10.2210/pdb2jxz/pdb |
| Descriptor | Calcitonin (1 entity in total) |
| Functional Keywords | a-helix, amidation, cleavage on pair of basic residues, hormone, secreted |
| Cellular location | Secreted: P01258 |
| Total number of polymer chains | 1 |
| Total formula weight | 3455.89 |
| Authors | Andreotti, G.,Vitale, R.,Avidan-Shpalter, C.,Amodeo, P.,Gazit, E.,Motta, A. (deposition date: 2007-12-03, release date: 2008-11-25, Last modification date: 2011-07-13) |
| Primary citation | Andreotti, G.,Vitale, R.M.,Avidan-Shpalter, C.,Amodeo, P.,Gazit, E.,Motta, A. Converting the highly amyloidogenic human calcitonin into a powerful fibril inhibitor by 3D structure homology with a non-amyloidogenic analogue J.Biol.Chem., 286:2707-2718, 2011 Cited by PubMed Abstract: Irreversible aggregation limits bioavailability and therapeutic activity of protein-based drugs. Here we show that an aggregation-resistant mutant can be engineered by structural homology with a non-amyloidogenic analogue and that the aggregation-resistant variant may act as an inhibitor. This strategy has successfully been applied to the amyloidogenic human calcitonin (hCT). Including only five residues from the non-amyloidogenic salmon calcitonin (sCT), we obtained a variant, polar human calcitonin (phCT), whose solution structure was shown by CD, NMR, and calculations to be practically identical to that of sCT. phCT was also observed to be a potent amyloidogenesis inhibitor of hCT when mixed with it in a 1:1 ratio. Fibrillation studies of phCT and the phCT-hCT mixture mimicked the sCT behavior in the kinetics and shapes of the fibrils with a dramatic reduction with respect to hCT. Finally, the effect of phCT alone and of the mixture on the intracellular cAMP level in T47D cells confirmed for the mutant and the mixture their calcitonin-like activity, exhibiting stimulation effects identical to those of sCT, the current therapeutic form. The strategy followed appears to be suitable to develop new forms of hCT with a striking reduction of aggregation and improved activity. Finally, the inhibitory properties of the aggregation-resistant analogue, if confirmed for other amyloidogenic peptides, may favor a new strategy for controlling fibril formation in a variety of human diseases. PubMed: 21078667DOI: 10.1074/jbc.M110.182014 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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