A proton NMR study of human calcitonin in solution

Motta, Andréa; Pa, Temussi; Wünsch, Erich; Bovermann, Günter

doi:10.1021/bi00223a010

Cited by 46 publications

(61 citation statements)

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“…In TFE-H 2 O mixtures, calcitonin forms α-helical structure between the residues 9 and 21 [309]. In DMSO-H 2 O, the central region (residues 16-21) of calcitonin might form a short double-stranded antiparallel β-sheet [310]. It was suggested that human calcitonin exhibits an amphiphilic nature when it forms an α-helix [311].…”

Section: Calcitonin and Medullary Thyroid Cancermentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.

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Section: Calcitonin and Medullary Thyroid Cancermentioning

confidence: 99%

Amyloidogenesis of Natively Unfolded Proteins

Uversky

2008

CAR

174

152

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“…in the central region made by residues 16-21 in DMSO0H 2 Õ Motta et al, 1991b!. It was suggested that hCT exhibits an amphiphilic nature when it forms an a-helix~Epand et al, 1983!.…”

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confidence: 99%

Conformational transitions and fibrillation mechanism of human calcitonin as studied by high‐resolution solid‐state ¹³C NMR

Kamihira

Naito²,

Tuzi³

et al. 2000

Protein Science

123

246

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Conformational transitions of human calcitonin~hCT! during fibril formation in the acidic and neutral conditions were investigated by high-resolution solid-state 13 C NMR spectroscopy. In aqueous acetic acid solution~pH 3.3!, a local a-helical form is present around Gly10, whereas a random coil form is dominant as viewed from Phe22, Ala26, and Ala31 in the monomer form on the basis of the 13 C chemical shifts. On the other hand, a local b-sheet form as viewed from Gly10 and Phe22, and both b-sheet and random coil as viewed from Ala26 and Ala31 were detected in the fibril at pH 3.3. The results indicate that conformational transitions from a-helix to b-sheet, and from random coil to b-sheet forms occurred in the central and C-terminus regions, respectively, during the fibril formation. The increased 13 C resonance intensities of fibrils after a certain delay time suggests that the fibrillation can be explained by a two-step reaction mechanism in which the first step is a homogeneous association to form a nucleus, and the second step is an autocatalytic heterogeneous fibrillation. In contrast to the fibril at pH 3.3, the fibril at pH 7.5 formed a local b-sheet conformation at the central region and exhibited a random coil at the C-terminus region. Not only a hydrophobic interaction among the amphiphilic a-helices, but also an electrostatic interaction between charged side chains can play an important role for the fibril formation at pH 7.5 and 3.3 acting as electrostatically favorable and unfavorable interactions, respectively. These results suggest that hCT fibrils are formed by stacking antiparallel b-sheets at pH 7.5 and a mixture of antiparallel and parallel b-sheets at pH 3.3.

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“…CD studies have shown that calcitonins have little ordered secondary structure in aqueous solutions. However, the CD spectrum displays a double trough, characteristic of A-helical structure, in the presence of phospholipids or trifluoroethanol [6,7].NMR studies on salmon calcitonin in aqueous trifluoroethanol [8] [14] in aqueous dimethylsulfoxide solutions take an extended conformation with only short double-stranded antiparallel β-sheet regions. We have recently reported that the conformation of elcatonin, a carba-type analogue of eel calcitonin (eCT) in which the disulfide bond has been replaced by an ethylene bridge, is characterized by an amphiphilic A-helix and some turn structure in the N-terminal region [15].…”

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confidence: 99%

“…NMR studies on salmon calcitonin in aqueous trifluoroethanol [8] [14] in aqueous dimethylsulfoxide solutions take an extended conformation with only short double-stranded antiparallel β-sheet regions. We have recently reported that the conformation of elcatonin, a carba-type analogue of eel calcitonin (eCT) in which the disulfide bond has been replaced by an ethylene bridge, is characterized by an amphiphilic A-helix and some turn structure in the N-terminal region [15].…”

mentioning

confidence: 99%

“…Also, human calcitonin [11] and human calcitonin analogue ([Leu12, Leu16, Leu19, Tyr22] calcitonin (human)) [12] have been shown to form an amphiphilic Ahelix in 40% trifluoroethanol solution. However, Motta et al have reported that salmon calcitonin [13] and human calcitonin [14] in aqueous dimethylsulfoxide solutions take an extended conformation with only short double-stranded antiparallel β-sheet regions. We have recently reported that the conformation of elcatonin, a carba-type analogue of eel calcitonin (eCT) in which the disulfide bond has been replaced by an ethylene bridge, is characterized by an amphiphilic A-helix and some turn structure in the N-terminal region [15].…”

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Conformation analysis of eel calcitonin

Ogawa

Nishimura

Uchiyama

et al. 1998

European Journal of Biochemistry

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The solution structure of eel calcitonin in a mixture of 60% water and 40% trifluoroethanol has been determined in this study by the combined use of 1 H-NMR spectroscopy and distance geometry calculations. 1 H-NMR spectroscopy provided 181 distance constraints, 5 dihedral angle constraints and 14 hydrogen bond constraints. The observed NOEs demonstrated the presence of an amphiphilic A-helix in position Leu4ϪGln20. The seven best converged structures exhibit backbone atomic rmsd of 0.027 nm for the backbone atoms from the averaged coordinate position in the region of Cys1ϪLeu19. In the previous study [Ogawa, K., Nishimura, S., Doi, M., Kyogoku, Y., Hayashi, M. & Kobayashi, Y. (1994) Eur. J. Biochem. 222, 659Ϫ666], the conformation of elcatonin, an analogue of eel calcitonin, was characterized by an amphiphilic A-helix between Thr6 and Thr21 and a turn structure in the first five residues of the N-terminus. The major difference of structure between eel calcitonin and elcatonin exists within the cyclic moiety at the helical N-terminus. Some of the turn structure detected at the N-terminus in elcatonin is not found in eel calcitonin. This is attributed to the difference in the ring formation caused by the disulfide bridge and ethylene bridge. A medium-range NOE, d AN (i,iϩ2), is detected between the CAH of Arg24 and the NH of Asp26, so a turn structure occurs in this segment. This NOE connectivity profile in the C-terminal region is also the same in elcatonin, suggesting that this is important for receptor binding and immunological properties.Keywords : calcitonin; eel calcitonin; amphiphilic A-helix; distance geometry; NMR.Calcitonin is an endogenous peptide produced by the parafollicular cells of the thyroid, parathyroid and thymus glands, which acts principally on bone as a regulator of calcium homeostasis. The therapeutic use of calcitonin is to treat disorders in calcium metabolism involving hypercalcemia, Paget's disease and osteoporosis. Calcitonin has been extracted from various species of animals and primary structures have been determined. Each of them consists of 32 amino acids, containing a disulfide bridge between two cysteine residues in positions 1 and 7 and a proline amide group at the C-terminal end. The physiology and pharmacology of calcitonin have been reviewed by Azria [1].In general, fish calcitonins have more potent biological activities than those of mammals [2]. Many studies on the relationship between structure and biological activity in salmon calcitonin have been carried out. Moe and Kaiser [3] have suggested that an amphiphilic A-helical structure plays an important role in binding to calcitonin receptors. Other structural features such as conformational flexibility have been associated with biological activity as well [4,5]. CD studies have shown that calcitonins have little ordered secondary structure in aqueous solutions. However, the CD spectrum displays a double trough, characteristic of A-helical structure, in the presence of phospholipids or trifluoroethanol [6,7].NMR studies on...

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A proton NMR study of human calcitonin in solution

Cited by 46 publications

References 50 publications

Amyloidogenesis of Natively Unfolded Proteins

Amyloidogenesis of Natively Unfolded Proteins

Conformational transitions and fibrillation mechanism of human calcitonin as studied by high‐resolution solid‐state ¹³C NMR

Conformation analysis of eel calcitonin

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A proton NMR study of human calcitonin in solution

Cited by 46 publications

References 50 publications

Amyloidogenesis of Natively Unfolded Proteins

Amyloidogenesis of Natively Unfolded Proteins

Conformational transitions and fibrillation mechanism of human calcitonin as studied by high‐resolution solid‐state 13C NMR

Conformation analysis of eel calcitonin

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Conformational transitions and fibrillation mechanism of human calcitonin as studied by high‐resolution solid‐state ¹³C NMR