Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Pascal Krotee; Jose A. Rodriguez; Michael R. Sawaya; Duilio Cascio; Francis E. Reyes; Dan Shi; Johan Hattne; Brent L. Nannenga; Marie E. Oskarsson; Stephan Philipp; Sarah Griner; Lin Jiang; Charles G. Glabe; Gunilla T. Westermark; Tamir Gonen; David S. Eisenberg

doi:10.7554/eLife.19273

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Pascal Krotee, Jose A. Rodriguez, Michael R. Sawaya, Duilio Cascio, Francis E. Reyes, Dan Shi, Johan Hattne, Brent L. Nannenga, Marie E. Oskarsson, Stephan Philipp, Sarah Griner, Lin Jiang, Charles G. Glabe, Gunilla T. Westermark, Tamir Gonen, David S. Eisenberg

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88 Scopus citations

Abstract

HIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19–29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15–25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19–29 S20G may serve as a model for the toxic spine of hIAPP.

Original language	English (US)
Article number	e19273
Journal	eLife
Volume	6
DOIs	https://doi.org/10.7554/eLife.19273
State	Published - Jan 3 2017
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.19273

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Krotee, P., Rodriguez, J. A., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., Hattne, J., Nannenga, B. L., Oskarsson, M. E., Philipp, S., Griner, S., Jiang, L., Glabe, C. G., Westermark, G. T., Gonen, T., & Eisenberg, D. S. (2017). Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity. eLife, 6, Article e19273. https://doi.org/10.7554/eLife.19273

Krotee, P, Rodriguez, JA, Sawaya, MR, Cascio, D, Reyes, FE, Shi, D, Hattne, J, Nannenga, BL, Oskarsson, ME, Philipp, S, Griner, S, Jiang, L, Glabe, CG, Westermark, GT, Gonen, T & Eisenberg, DS 2017, 'Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity', eLife, vol. 6, e19273. https://doi.org/10.7554/eLife.19273

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title = "Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity",

abstract = "HIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19–29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15–25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19–29 S20G may serve as a model for the toxic spine of hIAPP.",

author = "Pascal Krotee and Rodriguez, {Jose A.} and Sawaya, {Michael R.} and Duilio Cascio and Reyes, {Francis E.} and Dan Shi and Johan Hattne and Nannenga, {Brent L.} and Oskarsson, {Marie E.} and Stephan Philipp and Sarah Griner and Lin Jiang and Glabe, {Charles G.} and Westermark, {Gunilla T.} and Tamir Gonen and Eisenberg, {David S.}",

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year = "2017",

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doi = "10.7554/eLife.19273",

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AU - Krotee, Pascal

AU - Rodriguez, Jose A.

AU - Sawaya, Michael R.

AU - Cascio, Duilio

AU - Reyes, Francis E.

AU - Shi, Dan

AU - Hattne, Johan

AU - Nannenga, Brent L.

AU - Oskarsson, Marie E.

AU - Philipp, Stephan

AU - Griner, Sarah

AU - Jiang, Lin

AU - Glabe, Charles G.

AU - Westermark, Gunilla T.

AU - Gonen, Tamir

AU - Eisenberg, David S.

PY - 2017/1/3

Y1 - 2017/1/3

N2 - HIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19–29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15–25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19–29 S20G may serve as a model for the toxic spine of hIAPP.

AB - HIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19–29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15–25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19–29 S20G may serve as a model for the toxic spine of hIAPP.

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Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity

Abstract

ASJC Scopus subject areas

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