Document Detail

Insights into the disparate action of osmolytes and macromolecular crowders on amyloid formation.
MedLine Citation:
PMID:  22453174     Owner:  NLM     Status:  MEDLINE    
It is widely recognized that amyloid formation sensitively responds to conditions set by myriad cellular solutes. These cosolutes include two important classes: macromolecular crowders and compatible osmolytes. We have recently found that addition of macromolecular PEG only slightly affects fibril formation of a model peptide in vitro. Polyol osmolytes, in contrast, lengthen the lag time for aggregation, and lead to larger fibril mass at equilibrium. To further hypothesize on the molecular underpinnings of the disparate effect of the two cosolute classes, we have further analyzed the experiments using an available kinetic mechanism describing fibril aggregation. Model calculations suggest that all cosolutes similarly lengthen the time required for nucleation, possibly due to their excluded volume effect. However, PEGs may in addition promote fibril fragmentation, leading to lag times that are overall almost unvaried. Moreover, polyols effectively slow the monomer-fibril detachment rates, thereby favoring additional fibril formation. Our analysis provides first hints that cosolutes act not only by changing association or dissociation rates, but potentially also by directing the formation of fibrils of varied morphologies with different mechanical properties. Although additional experiments are needed to unambiguously resolve the action of excluded cosolutes on amyloid formation, it is becoming clear that these compounds are important to consider in the search for ways to modulate fibril formation.
Shahar Sukenik; Daniel Harries
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Prion     Volume:  6     ISSN:  1933-690X     ISO Abbreviation:  Prion     Publication Date:    2012 Jan-Mar
Date Detail:
Created Date:  2012-03-28     Completed Date:  2012-08-10     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101472305     Medline TA:  Prion     Country:  United States    
Other Details:
Languages:  eng     Pagination:  26-31     Citation Subset:  IM    
Institute of Chemistry and the Fritz Haber Research Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
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MeSH Terms
Amyloid / chemistry,  drug effects*,  metabolism*
Macromolecular Substances / pharmacology*
Models, Biological
Polymers / pharmacology*
Protein Structure, Quaternary
Thiazoles / metabolism
Reg. No./Substance:
0/Amyloid; 0/Macromolecular Substances; 0/Polymers; 0/Thiazoles; 0/polyol; 2390-54-7/thioflavin T

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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