NDLI: Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

Content Provider	PubMed Central
Author	Rodrigues, J. Rui Silva, Cândida G. Brito, Rui M. M. Simões, Carlos J. V.
Abstract	Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt-Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT-TTR and L55P-TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P-TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α-helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation-prone conformations characterized by full displacement of strands C and D from the main β-sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H-bond network and consequent destabilization of the CBEF β-sheet of the β-sandwich; (v) WT forms aggregation-compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P-TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.
Related Links	http://dx.doi.org/10.1002/pro.289
Starting Page	202
File Format	PDF
ISSN	1469896X
e-ISSN	1469896X
Journal	Protein Science : A Publication of the Protein Society
Issue Number	2
Volume Number	19
Language	English
Publisher	Wiley Subscription Services, Inc., A Wiley Company
Publisher Date	2010-02-01
Access Restriction	Open
Rights Holder	Wiley Subscription Services, Inc., A Wiley Company
Subject Keyword	Proteomics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine Molecular Biology Biochemistry

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