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Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation
Othmer-Jacobs Department of Chemical and Biomolecular Engineering, Polytechnic Institute of New York University, 6 MetroTech Center, Brooklyn, New York 11201, USA
* Author to whom correspondence should be addressed.
Received: 10 August 2012; in revised form: 13 September 2012 / Accepted: 13 September 2012 / Published: 25 September 2012
Abstract: Peptide/protein aggregation is implicated in many amyloid diseases. Some amyloidogenic peptides/proteins, such as those implicated in Alzheimer’s and Parkinson’s diseases, contain multiple amyloidogenic domains connected by “linker” sequences displaying high propensities to form turn structures. Recent studies have demonstrated the importance of physicochemical properties of each amino acid contained in the polypeptide sequences in amyloid aggregation. However, effects on aggregation related to the intramolecular distance between amyloidogenic domains, which may be determined by a linker length, have yet to be examined. In the study presented here, we created peptides containing two copies of KFFE, a simple four-residue amyloidogenic domain, connected by GS-rich linker sequences with different lengths yet similar physicochemical properties. Our experimental results indicate that aggregation occurred most rapidly when KFFE domains were connected by a linker of an intermediate length. Our experimental findings were consistent with estimated entropic contribution of a linker length toward formation of (partially) structured intermediates on the aggregation pathway. Moreover, inclusion of a relatively short linker was found to inhibit formation of aggregates with mature fibril morphology. When the results are assimilated, our study demonstrates that intramolecular distance between amyloidogenic domains is an important yet overlooked factor affecting amyloid aggregation.
Keywords: amyloid; fibril; peptide aggregation; KFFE
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MDPI and ACS Style
Ko, A.; Kim, J.R. Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation. Int. J. Mol. Sci. 2012, 13, 12169-12181.
Ko A, Kim JR. Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation. International Journal of Molecular Sciences. 2012; 13(10):12169-12181.
Ko, Ahra; Kim, Jin Ryoun. 2012. "Effects of Intramolecular Distance between Amyloidogenic Domains on Amyloid Aggregation." Int. J. Mol. Sci. 13, no. 10: 12169-12181.