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

Author:

Krotee Pascal1234ORCID,Rodriguez Jose A124,Sawaya Michael R124ORCID,Cascio Duilio124ORCID,Reyes Francis E5,Shi Dan5,Hattne Johan5ORCID,Nannenga Brent L5,Oskarsson Marie E6,Philipp Stephan7,Griner Sarah124,Jiang Lin389,Glabe Charles G710,Westermark Gunilla T6,Gonen Tamir5,Eisenberg David S1234

Affiliation:

1. Department of Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

2. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States

3. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States

4. UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, United States

5. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States

6. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

7. Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States

8. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

9. Brain Research Institute (BRI), University of California, Los Angeles, Los Angeles, United States

10. Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

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.

Funder

National Institutes of Health

Howard Hughes Medical Institute

Vetenskapsrådet

Swedish Diabetes Foundation

Cure Alzheimer's Fund

Publisher

eLife Sciences Publications, Ltd

Subject

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

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3