Channel Formation by Salmon and Human Calcitonin in Black Lipid Membranes

Stipani, Valentina; Gallucci, E.; Micelli, S.; Picciarelli, V.; Benz, Roland

doi:10.1016/s0006-3495(01)75966-8

Cited by 39 publications

(30 citation statements)

References 37 publications

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“…Other studies have confirmed those observations [10], and furthermore correlated channel formation with sterol presence in lipid bilayers [11]. Channel assembly induced by other fibrillar proteins, such as Prion [12] and Calcitonin [13] were detected through application of the BLM methodology.…”

Section: Black Lipid Membranessupporting

confidence: 58%

“…Through analysis of linewidths and spectral shifts of the 31 P peak corresponding to the bilayer-forming phospholipids the authors showed that negative potential of the membrane interface is the driving force for the lipid-induced peptide fibrillation. While 31 P NMR generally provided information regarding structural modifications of lipid bilayers upon peptide interactions, 13 C NMR (specifically through application of cross-polarization magic angle spinning, CPMAS) has been a useful tool for elucidating binding and reorganization of the amyloid pep- Fig. (2).…”

Section: Nuclear Magnetic Resonance (Nmr) and Electronic Paramagneticmentioning

confidence: 99%

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Amyloid – Membrane Interactions: Experimental Approaches and Techniques

Jelinek¹,

Sheynis

2010

CPPS

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The growing interest in membrane interactions of amyloidogenic peptides and proteins emanates from the realization that lipids and membranes play important, potentially central, roles in the toxicity and pathological pathways of amyloid diseases. Expanding body of evidence indicates that lipid binding of amyloidogenic peptides and amyloid peptide association with cellular membranes is critical in the onset and progression of amyloid diseases. Advancing the understanding in this field goes hand in hand with application of varied biophysical and biological techniques designed to probe the characteristics and underlying mechanisms of membrane-peptide interactions. This review summarizes experimental approaches and technical aspects employed in recent years for investigating the interaction of amyloid peptides and fibrillar species with lipid bilayers, and the reciprocal contribution of membranes to fibrillation processes and amyloidogenesis.

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Section: Black Lipid Membranessupporting

confidence: 58%

Section: Nuclear Magnetic Resonance (Nmr) and Electronic Paramagneticmentioning

confidence: 99%

Amyloid – Membrane Interactions: Experimental Approaches and Techniques

Jelinek¹,

Sheynis

2010

CPPS

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“…3c). This finding can be related to longer-term receptor activation, as it is the case for sCT, perhaps associated with an increased facility of the CT variants to interact with membrane lipids (42,43). Such an observation could have important repercussions in the use of these reengineered variants as therapeutics.…”

Section: Resultsmentioning

confidence: 94%

Rational design of aggregation-resistant bioactive peptides: Reengineering human calcitonin

Fowler

Poon

Muff

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

103

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A high propensity to aggregate into intractable deposits is a common problem limiting the production and use of many peptides and proteins in a wide range of biotechnological and pharmaceutical applications. Many therapeutic polypeptides are frequently abandoned at an early stage in their development because of problems with stability and aggregation. It has been shown recently that parameters describing the physicochemical properties of polypeptides can be used as predictors of protein aggregation. Here we demonstrate that these and similar tools can be applied to the rational redesign of bioactive molecules with a significantly reduced aggregation propensity without loss of physiological activity. This strategy has been exemplified by designing variants of the hormone calcitonin that show a significantly reduced aggregation propensity, yet maintain, or even increase, their potency when compared to the current therapeutic forms. The results suggest that this approach could be used successfully to enhance the solubility and efficacy of a wide range of other peptide and protein therapeutics.protein aggregation ͉ protein design ͉ biopharmaceuticals ͉ amyloid ͉ misfolding T he number of pharmacologically active peptides and proteins under development for the prevention and treatment of human disorders is increasing, and as a result, so is the pressure to overcome problems associated with aggregation and stability. Up to 96% of all drug candidates in trials are abandoned during preclinical or clinical development, often because of low solubility or aggregation problems (1). Many peptide-based drugs with great therapeutic potential are rendered ineffective simply because of an intrinsic propensity to aggregate irreversibly (2). Aggregation is one of the most significant obstacles to the development of protein-based drugs because it cannot only compromise their bioavailability and therapeutic activity but it may also increase the risk of immunogenic reactions (3, 4).A good example of a bioactive peptide with limited pharmaceutical potential due to a high tendency to aggregate is human calcitonin (hCT), a 32-residue polypeptide hormone synthesized and secreted by the C cells of the thyroid, and involved in calcium regulation and bone dynamics. In vivo, calcitonin (CT) causes a rapid, but short-lived, decline in calcium and phosphate levels in the blood by promoting the incorporation of these ions into bone (5). This activity has lead to the use of CT in the treatment of conditions such as osteoporosis and Paget's disease, as well as malignancy-caused hypercalcemia and musculoskeletal pain (5-7). However, hCT shows an extremely high tendency to selfassociate in the form of amyloid fibrils. As a result hCT amyloid deposits can occur in vivo in patients with medullar carcinoma of the thyroid (8, 9) and in vitro in preparations designed for patient administration (10). Not only does aggregation constitute a serious problem during the production, storage, and administration of hCT, but it can also lead to a significant decr...

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“…Although the sequences of these peptides are somewhat dissimilar, all the peptides in this family bind to common G-coupled protein receptors and produce similar effects in many tissues 54,55. Many of the peptides in this family such as human CGRP and calcitonin are also amyloidogenic and aggregate to form membrane-disruptive oligomeric structures 56–59. NMR studies on these peptides in detergent micelles have shown that these properties are apparently linked to common structural elements held among the family.…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Structure and Orientation of Rat Islet Amyloid Polypeptide Protein in a Membrane Environment by Solution NMR Spectroscopy

et al. 2009

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Islet amyloid polypeptide (IAPP or amylin) is a 37-residue peptide hormone associated with glucose metabolism that is cosecreted with insulin by β-cells in the pancreas. Since human IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers is responsible for the death of β-cells during the early stages of type II diabetes. It has been hypothesized that transient membrane-bound α-helical structures of human IAPP are precursors to the formation of these amyloid deposits. On the other hand, rat IAPP forms transient α-helical structures but does not progress further to form amyloid fibrils. To understand the nature of this intermediate state and the difference in toxicity between the rat and human versions of IAPP, we have solved the high-resolution structure of rat IAPP in the membrane-mimicking detergent micelles composed of dodecylphosphocholine. The structure is characterized by a helical region spanning the residues A5 to S23 and a disordered C-terminus. A distortion in the helix is seen at R18 and S19 that may be involved in receptor binding. Paramagnetic quenching NMR experiments indicate that rat IAPP is bound on the surface of the micelle, in agreement with other nontoxic forms of IAPP. A comparison to the detergent-bound structures of other IAPP variants indicates that the N-terminal region may play a crucial role in the self-association and toxicity of IAPP by controlling access to the putative dimerization interface on the hydrophobic face of the amphipathic helix.

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Channel Formation by Salmon and Human Calcitonin in Black Lipid Membranes

Cited by 39 publications

References 37 publications

Amyloid – Membrane Interactions: Experimental Approaches and Techniques

Amyloid – Membrane Interactions: Experimental Approaches and Techniques

Rational design of aggregation-resistant bioactive peptides: Reengineering human calcitonin

Three-Dimensional Structure and Orientation of Rat Islet Amyloid Polypeptide Protein in a Membrane Environment by Solution NMR Spectroscopy

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