Chapter 7 A New Class of Peptide-Forming Channel

Micelli, S.; Meleleo, Daniela; Tien, H. Ti; Liu, Angelica Leitmannova; Picciarelli, V.; Gallucci, E.

doi:10.1016/s1554-4516(08)00007-0

Cited by 3 publications

(4 citation statements)

References 69 publications

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“…IAPP belongs to the CGRP family of peptides that includes calcitonin-gene-related peptide (CGRP), calcitonin, adrenomodulin, and IAPP . 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. , Many of the peptides in this family such as human CGRP and calcitonin are also amyloidogenic and aggregate to form membrane-disruptive oligomeric structures. − NMR studies on these peptides in detergent micelles have shown that these properties are apparently linked to common structural elements held among the family. All of the peptides in this family possess an amidated C-terminus, an amphipathic helix near the N-terminus, a largely disordered C-terminus, and an N-terminal ring connected by a disulfide bond. − Two binding sites have been proposed for the binding of peptides of this family to the membrane-bound receptor: one near the membrane surface that would be consistent with the orientation found in this study for rIAPP and another requiring a more deeply inserted membrane orientation as found for hIAPP 1−19 and hypothesized for hIAPP. ,, Relatively little is known about structure−activity relationships for IAPP’s normal biological action in comparison to its pathological aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…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][57][58][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. All of the peptides in this family possess an amidated C-terminus, an amphipathic helix near the N-terminus, a largely disordered C-terminus, and an N-terminal ring connected by a disulfide bond.…”

Section: Significance Of the Structure For The Normal Biologicalmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Significance Of the Structure For The Normal Biologicalmentioning

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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“…The specifics of the progression from α‐helical intermediates toward the mature fibrillar structure are influenced by a number of factors, including pH conditions, the presence of lipids, buffer composition, and the concentrations and types of salts and metal ions ,,,,,. Despite this variability in fibrillation, α‐helical intermediates have been observed under a range of conditions, and play a significant role in the biological function of CT ,,,,. Regarding the α‐helical intermediate, it is reported that dimerization of hCT stabilize the α‐helix under aqueous TFE solutions, leading to the long fibril formation .…”

Section: Structural Studies On Calcitonin Aggregationmentioning

confidence: 99%

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

Kamgar-Parsi

Tolchard

Habenstein

et al. 2016

Israel Journal of Chemistry

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Under appropriate conditions, peptides and proteins can assemble from their native state into prefibrillar oligomers and then mature into fibrillar aggregates. This transition forms the molecular basis of several pathologies, often related to the deposition of these amyloid fibrils. Several hormone peptides involved in fundamental biological processes have the tendency to self‐assemble into amyloid fibrils, resulting in a loss of their native functions, and more importantly, entailing devastating consequences, such as the formation of amyloid depositions. Calcitonin is a 32 amino‐acid hormone peptide that can be considered a molecular paradigm for the central events associated with hormone misfolding. Calcitonin in its native form is involved in various physiological functions, including mediating calcium homeostasis and maintaining bone structure. It is the latter function that has motivated the use of calcitonin as an aqueous therapeutic agent for the treatment of bone‐related pathologies such as osteoporosis and Paget's disease. Despite some success as a therapeutic, calcitonin's ability to control these diseases is limited by its aggregation along the canonical amyloid aggregation pathway, compromising its long‐term stability as a therapeutic agent. A better understanding of the misfolding process would not only provide the structural basis to improve calcitonin's long‐term stability and activity as a therapeutic, but also provide valuable insights into pathological aggregation of other amyloids. In this work, we review the physiological roles of calcitonin, its structure, and aggregation process, and consider the effects of calcitonin's structure on its role as a therapeutic.

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“…For instance, exposing osteoclasts to high doses of extracellular Ca 2ϩ during active bone resorption triggers increases in the [Ca 2ϩ ] i and inhibits osteoclast function, in a self-modulated loop (3). In addition, osmotic membrane stretches, environmental acidification, or temperature changes all induce increased [Ca 2ϩ ] i (4,5). The signaling pathways and metabolic cell functions most commonly reported to be affected by such increases in Ca 2ϩ in the cytosol are perturbations of the resorbing machinery, with a direct inhibition of acid secretion (6 -8).…”

mentioning

confidence: 99%

TRPV-5 Mediates a Receptor Activator of NF-κB (RANK) Ligand-induced Increase in Cytosolic Ca2+ in Human Osteoclasts and Down-regulates Bone Resorption

Chamoux

Bisson

Payet

et al. 2010

Journal of Biological Chemistry

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Chapter 7 A New Class of Peptide-Forming Channel

Cited by 3 publications

References 69 publications

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

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

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

TRPV-5 Mediates a Receptor Activator of NF-κB (RANK) Ligand-induced Increase in Cytosolic Ca2+ in Human Osteoclasts and Down-regulates Bone Resorption

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