2019
DOI: 10.1038/s41594-019-0238-6
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The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations

Abstract: Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia in diabetic patients, respectively. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility, and is therefore formulated as a lyophilized powder that is reconstituted in acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown… Show more

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Cited by 68 publications
(95 citation statements)
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“…To investigate the possible structures that are consistent with these experimental chemical shifts and long-range contacts, we conducted structure calculations for residues 268 to 340 in XPLOR-NIH (40), using chemical-shift restrained torsion angles and the sparse long-range contacts as input parameters. We assume parallel-in-register intermolecular packing, which is found in most amyloid fibrils to date (41). The lowest-energy structural model is shown in Fig.…”
Section: N4r Tau Forms a Single Ultrastructural Fibril Morphology Inmentioning
confidence: 99%
“…To investigate the possible structures that are consistent with these experimental chemical shifts and long-range contacts, we conducted structure calculations for residues 268 to 340 in XPLOR-NIH (40), using chemical-shift restrained torsion angles and the sparse long-range contacts as input parameters. We assume parallel-in-register intermolecular packing, which is found in most amyloid fibrils to date (41). The lowest-energy structural model is shown in Fig.…”
Section: N4r Tau Forms a Single Ultrastructural Fibril Morphology Inmentioning
confidence: 99%
“…The fibrils of this protein also present a high pH dependence with respect to stability [ 155 ]. Proteins such as the Hen-egg lysozyme [ 156 ], the regulatory ATPase variant A (RavA) from E.coli [ 157 ], TTR [ 158 ], serum amyloid A [ 159 ], insulin [ 160 ], and glucagon [ 161 ], among others, have been shown to aggregate at acidic conditions (pH = 2–5), where the transition to a β-sheet structure upon oligomerization and amyloid aggregation was observed. However, other peptides and proteins, such as the designed EASZ model peptide [ 162 ], Ac-Phe-Phe-Cys-NH 2 (Ac-FFC-NH 2 ) [ 61 ] amyloid peptide model, and some peptides from human Pbx-regulating protein-1, have been shown to aggregate to β-sheet structure at basic pHs [ 163 ].…”
Section: Circular Dichroism Makes It Possible To Follow Secondary mentioning
confidence: 99%
“…This is likely due to a variety of distinct but simultaneous intermediate steps occurring within the same aggregation reaction 15 . Differences in morphology often reflect different molecular arrangements and physicalchemical features [16][17][18][19][20][21][22] . Variations in 1) the number of protofilaments constituting the mature fibril, 2) the relative arrangement of the protofilaments and 3) the molecular structure of the protofilament are reported as the main sources of such variability 23,24 .…”
Section: Introductionmentioning
confidence: 99%