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Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: insights from molecular dynamics simulations.

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 alpha-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 beta-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 beta-sheet of the beta-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.

SUBMITTER: Rodrigues JR

PROVIDER: S-EPMC2865717 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: insights from molecular dynamics simulations.

Rodrigues J Rui JR Simões Carlos J V CJ Silva Cândida G CG Brito Rui M M RM

Protein science : a publication of the Protein Society 20100201 2

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 unfold ...[more]

PMID: 19937650

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Project description:The amyloid aggregation of human islet amyloid polypeptide (hIAPP) is associated with pancreatic β-cell death in type 2 diabetes. The S20G substitution of hIAPP (hIAPP(S20G)), found in Japanese and Chinese people, is more amyloidogenic and cytotoxic than wild-type hIAPP. Rat amylin (rIAPP) does not have aggregation propensity or cytotoxicity. Mounting evidence suggests that soluble low-molecular-weight amyloid oligomers formed during early aggregation are more cytotoxic than mature fibrils. The self-assembly dynamics and oligomeric conformations remain unknown because the oligomers are heterogeneous and transient. The molecular mechanism of sequence-variation rendering dramatically different aggregation propensity and cytotoxicity is also elusive. Here, we investigate the oligomerization dynamics and conformations of amyloidogenic hIAPP, hIAPP(S20G), and non-amyloidogenic rIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our simulation results demonstrated that all three monomeric amylin peptides mainly adopted an unstructured formation with partial dynamical helices near the N-terminus. Relatively transient β-hairpins were more abundant in hIAPP and hIAPP(S20G) than in rIAPP. The S20G-substituting mutant of hIAPP altered the turn region of the β-hairpin motif, resulting in more hydrophobic residue-pairwise contacts within the β-hairpin. Oligomerization dynamic investigation revealed that all three peptides spontaneously accumulated into helix-populated oligomers. The conformational conversion to form β-sheet-rich oligomers was only observed in hIAPP and hIAPP(S20G). The population of high-β-sheet-content oligomers was enhanced by S20G substitution. Interestingly, both hIAPP and hIAPP(S20G) could form β-barrel formations, and the β-barrel propensity of hIAPP(S20G) was three times larger than that of hIAPP. No β-sheet-rich or β-barrel formations were observed in rIAPP. Our direct observation of the correlation between β-barrel oligomer formation and cytotoxicity suggests that β-barrels might play a critically important role in the cytotoxicity of amyloidosis.

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Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: insights from molecular dynamics simulations.

Publications

Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: insights from molecular dynamics simulations.

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