Conformation of a Peptide Corresponding to T4 Lysozyme Residues 59-81 by NMR and CD Spectroscopy

McLeish, Michael J.; Nielsen, Katherine J.; Najbar, Lidia V.; Wade, John D.; Lin, Feng; Doughty, Michael B.; Craik, David J.

doi:10.1021/bi00203a013

Cited by 35 publications

(41 citation statements)

References 60 publications

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“…This implies that either the NMR data are not sufficient to define the relative orientations of sections of the helix, or that the long helix has genuine flexibility. The high degree of curvature observed in most of our structures is not surprising, as this is commonly observed for amphipathic helices in solution (33,34). Analysis of the backbone H-bonds shows that all structures contain a mixture of i,iϩ3, and i,iϩ4 interactions, consistent with 3 10 and ␣-helix, respectively, where the 3 10 helix component consists of approximately 38% of the total backbone H-bonds.…”

Section: Three-dimensional Structure Of Conantokin Peptidessupporting

confidence: 69%

Determination of the Solution Structures of Conantokin-G and Conantokin-T by CD and NMR Spectroscopy

Skjærbæk

Nielsen

Lewis

et al. 1997

Journal of Biological Chemistry

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Conantokin-G and conantokin-T are two paralytic polypeptide toxins originally isolated from the venom of the fish-hunting cone snails of the genus Conus. Conantokin-G and conantokin-T are the only naturally occurring peptidic compounds which possess N-methyl-D-aspartate receptor antagonist activity, produced by a selective non-competitive antagonism of polyamine responses. They are also structurally unusual in that they contain a disproportionately large number of acid labile post-translational ␥-carboxyglutamic acid (Gla) residues. Although no precise structural information has previously been published for these peptides, early spectroscopic measurements have indicated that both conantokin-G and conantokin-T form ␣-helical structures, although there is some debate whether the presence of calcium ions is required for these peptides to adopt this fold. We now report a detailed structural study of synthetic conantokin-G and conantokin-T in a range of solution conditions using CD and 1 H NMR spectroscopy. The three-dimensional structures of conantokin-T and conantokin-G were calculated from 1 H NMR-derived distance and dihedral restraints. Both conantokins were found to contain a mixture of ␣-and 3 10 helix, that give rise to curved and straight helical conformers.

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Section: Three-dimensional Structure Of Conantokin Peptidessupporting

confidence: 69%

Determination of the Solution Structures of Conantokin-G and Conantokin-T by CD and NMR Spectroscopy

Skjærbæk

Nielsen

Lewis

et al. 1997

Journal of Biological Chemistry

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“…Periodicity is also observed for the HN chemical shifts (Fig. 2D), and this type of periodicity has been attributed to ␣-helix curvature (41,42). The secondary H␣ shifts, which are the most sensitive to secondary structure, appear to be on a gradient decreasing from residues 8 to 28 (Fig.…”

Section: Amylin Adopts An ␣-Helical Structure In the Presence Of Sdsmentioning

confidence: 72%

Dynamic α-Helix Structure of Micelle-bound Human Amylin

Patil

Sheftic

et al. 2009

Journal of Biological Chemistry

177

219

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Amylin is an endocrine hormone that regulates metabolism. In patients afflicted with type 2 diabetes, amylin is found in fibrillar deposits in the pancreas. Membranes are thought to facilitate the aggregation of amylin, and membrane-bound oligomers may be responsible for the islet ␤-cell toxicity that develops during type 2 diabetes. To better understand the structural basis for the interactions between amylin and membranes, we determined the NMR structure of human amylin bound to SDS micelles. The first four residues in the structure are constrained to form a hairpin loop by the single disulfide bond in amylin. The last nine residues near the C terminus are unfolded. The core of the structure is an ␣-helix that runs from about residues 5-28. A distortion or kink near residues 18 -22 introduces pliancy in the angle between the N-and C-terminal segments of the ␣-helix. Mobility, as determined by 15 N relaxation experiments, increases from the N to the C terminus and is strongly correlated with the accessibility of the polypeptide to spin probes in the solution phase. The spin probe data suggest that the segment between residues 5 and 17 is positioned within the hydrophobic lipid environment, whereas the amyloidogenic segment between residues 20 and 29 is at the interface between the lipid and solvent. This orientation may direct the aggregation of amylin on membranes, whereas coupling between the two segments may mediate the transition to a toxic structure. Type 2 diabetes affects over 100 million people worldwide (1) and is thought to cost upward of $130 billion dollars a year to treat in the United States alone (2). The endocrine hormone amylin (also known as islet amyloid polypeptide) appears to have key roles in diabetes pathology (3-5). The normal functions of amylin include the inhibition of glucagon secretion, slowing down the emptying of the stomach, and inducing a feeling of satiety through the actions of the hormone on neurons of the hypothalamus in the brain (5). The effects of amylin are exerted in concert with those of insulin and reduce the level of glucose in the blood (3, 5). Circulating amylin levels increase in a number of pathological conditions, including obesity, syndrome X, pancreatic cancer, and renal failure (3). Amylin levels together with insulin are raised initially in type 2 diabetes but fall as the disease progresses to a stage where the pancreatic islets of Langerhans ␤-cells that synthesize amylin no longer function (3).One of the hallmarks of type 2 diabetes, found in 90% of patients, is the formation of extracellular amyloid aggregates composed of amylin (3-5). The amyloid deposits accumulate in the interstitial fluid between islet cells and are usually juxtaposed with the ␤-cell membranes (3). Aggregates of amylin are toxic when added to cultures of ␤-cells, so that the amyloid found in situ may be responsible for ␤-cell death as type 2 diabetes progresses (6, 7). Genetic evidence that amylin is directly involved in pathology includes a familial S20G mutation that leads to early ...

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“…However, in 100% TFE PrP(121-127) adopted a random coil conformation, indicating that this peptide lacks a helical turn propensity. TFE titration offers a good method for analyzing the helical propensity of peptides (Chakrabartty et al, 1993;McLeish et al, 1994Merukta et al, 1990Nelson and Kallenbach, 1986;Satheeshkumar and Jayakumar, 2003). Fezoui and Teplow (2002) observed that the percentage of helical content increased in Ab 1À42 with increased TFE concentration.…”

Section: Resultsmentioning

confidence: 99%

Assemblages of prion fragments: novel model systems for understanding amyloid toxicity

Satheeshkumar

Jayaraman

Rajadas

2004

Journal of Structural Biology

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Conformation of a Peptide Corresponding to T4 Lysozyme Residues 59-81 by NMR and CD Spectroscopy

Cited by 35 publications

References 60 publications

Determination of the Solution Structures of Conantokin-G and Conantokin-T by CD and NMR Spectroscopy

Determination of the Solution Structures of Conantokin-G and Conantokin-T by CD and NMR Spectroscopy

Dynamic α-Helix Structure of Micelle-bound Human Amylin

Assemblages of prion fragments: novel model systems for understanding amyloid toxicity

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