@article{b60b0e11d7e34011977f094112f05cdd,
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.}",
note = "Funding Information: We thank Dan Anderson for suggesting the use of FEM maps. We thank the Advanced Photon Source (APS) staff for beamline support during collection of fiber diffraction: M. Capel, K. Rajashankar, N. Sukumar, J. Schuermann, I. Kourinov and F. Murphy at NECAT beam lines 24-ID; the UCLA-DOE X-ray Crystallography Core Technology Center, Michael Collazo, and the UCLA-DOE Macro-molecular Crystallization Core Technology Center for setting up initial crystallization screens; Ivo Atanasov and the Electron Imaging Center for NanoMachines (EICN) of California NanoSystems Institute (CNSI) at UCLA for the use of their electron microscopes; and the UCLA Statistical Consulting group for guidance on statistical computing. The UCLA-DOE X-ray and Macromolecular and Macromolecular Crystallization Core Technology Centers are supported in part by the Department of Energy grant DE-FC0302ER63421. Use of the Advanced Photon Source is supported by National Institutes of Health grants P41 RR015301 and P41 GM103403 and Department of Energy under Contract DE-AC02-06CH11357. We thank the Cure Alzheimer{\textquoteright}s Fund, the Swedish Research Council (VR 2015–02297), the Swedish Diabetes Foundation, the Janelia Research Campus visitor program, HHMI, and the National Institutes of Health (NIH) (R01 AG029430) for support. Publisher Copyright: {\textcopyright} Krotee et al.",
year = "2017",
month = jan,
day = "3",
doi = "10.7554/eLife.19273",
language = "English (US)",
volume = "6",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}