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TitleAtomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.
Journal, issue, pagesElife, Vol. 6, Year 2017
Publish dateJan 3, 2017
AuthorsPascal 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 /
PubMed AbstracthIAPP 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- ...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.
External linksElife / PubMed:28045370 / PubMed Central
MethodsEM (electron crystallography)
Resolution1.4 - 1.9 Å
Structure data

EMDB-8272, PDB-5knz:
Human Islet Amyloid Polypeptide Segment 19-SGNNFGAILSS-29 with Early Onset S20G Mutation Determined by MicroED
Method: EM (electron crystallography) / Resolution: 1.9 Å

EMDB-8273, PDB-5ko0:
Human Islet Amyloid Polypeptide Segment 15-FLVHSSNNFGA-25 Determined by MicroED
Method: EM (electron crystallography) / Resolution: 1.4 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-SCN:
THIOCYANATE ION / Thiocyanate

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Amyloid / islet amyloid polypeptide / Type II Diabetes / Toxic Spine / MicroED

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