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BIOLOGICAL SCIENCES / BIOPHYSICS
Fiber-dependent amyloid formation as catalysis of an existing reaction pathway

Amy M. Ruschak^* and Andrew D. Miranker^,

Departments of *Chemistry and Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114

Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved June 5, 2007 (received for review April 10, 2007)

A central component of a number of degenerative diseases is the deposition of protein as amyloid fibers. Self-assembly of amyloid occurs by a nucleation-dependent mechanism that gives rise to a characteristic sigmoidal reaction profile. The abruptness of this transition is a variable characteristic of different proteins with implications to both chemical mechanism and the aggressiveness of disease. Because nucleation is defined as the rate-limiting step, we have sought to determine the nature of this step for a model system derived from islet amyloid polypeptide. We show that nucleation occurs by two pathways: a fiber-independent (primary) pathway and a fiber-dependent (secondary) pathway. We first show that the balance between primary and secondary contributions can be manipulated by an external interface. Specifically, in the presence of this interface, the primary mechanism dominates, whereas in its absence, the secondary mechanism dominates. Intriguingly, we determine that both the reaction order and the enthalpy of activation of the two nucleation processes are identical. We interrogate this coincidence by global analysis using a simplified model generally applicable to protein polymerization. A physically reasonable set of parameters can be found to satisfy the coincidence. We conclude that primary and secondary nucleation need not represent different processes for amyloid formation. Rather, they are alternative manifestations of the same, surface-catalyzed nucleation event.

amylin | fibers | islet amyloid polypeptide | nucleation

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0703306104/DC1.

To whom correspondence should be addressed. E-mail: andrew.miranker{at}yale.edu

© 2007 by The National Academy of Sciences of the USA

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