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The Amyloid Formation Mechanism in Human IAPP: Dimers Have β-Strand Monomer−Monomer Interfaces
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Section:Abstract
Early oligomerization of human IAPP (hIAPP) is responsible for β-cell death in the pancreas and is increasingly considered a primary pathological process linked to Type II Diabetes (T2D). Yet, the assembly mechanism remains poorly understood, largely due to the inability of conventional techniques to probe distributions or detailed structures of early oligomeric species. Here, we describe the first experimental data on the isolated and unmodified dimers of human (hIAPP) and nonamyloidogenic rat IAPP (rIAPP). The experiments reveal that the human IAPP dimers are more extended than those formed by rat IAPP and likely descend from extended monomers. Independent all-atom molecular dynamics simulations show that rIAPP forms compact helix and coil rich dimers, whereas hIAPP forms β-strand rich dimers that are generally more extended. Also, the simulations reveal that the monomer−monomer interfaces of the hIAPP dimers are dominated by β-strands and that β-strands can recruit coil or helix structured regions during the dimerization process. Our β-rich interface contrasts with an N-terminal helix-to-helix interface proposed in the literature but is consistent with existing experimental data on the self-interaction pattern of hIAPP, mutation effects, and inhibition effects of the N-methylation in the mutation region.
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This article has been cited by 2 ACS Journal articles (2 most recent appear below).
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Thomas Wyttenbach and Michael T. BowersThe Journal of Physical Chemistry B2011 115 (42), 12266-12275The conformations of desolvated ubiquitin ions, lifted into the gas phase by electrospray ionization (ESI), were characterized by ion mobility spectrometry (IMS) and compared to the solution structures they originated from. The IMS instrument combining a ...
2DIR Spectroscopy of Human Amylin Fibrils Reflects Stable β-Sheet Structure
Lu Wang, Chris T. Middleton, Sadanand Singh, Allam S. Reddy, Ann M. Woys, David B. Strasfeld, Peter Marek, Daniel P. Raleigh, Juan J. de Pablo, Martin T. Zanni, and James L. SkinnerJournal of the American Chemical Society2011 133 (40), 16062-160712DIR Spectroscopy of Human Amylin Fibrils Reflects Stable β-Sheet Structure
Lu Wang, Chris T. Middleton, Sadanand Singh, Allam S. Reddy, Ann M. Woys, David B. Strasfeld, Peter Marek, Daniel P. Raleigh, Juan J. de Pablo, Martin T. Zanni, and James L. SkinnerJournal of the American Chemical Society2011 133 (40), 16062-16071The aggregation of human amylin to form amyloid contributes to islet β-cell dysfunction in type 2 diabetes. Studies of amyloid formation have been hindered by the low structural resolution or relatively modest time resolution of standard methods. Two-...
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History
- Published In Issue May 18, 2011
- Article ASAPApril 25, 2011
- Received: September 15, 2010
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