Dataset Information

The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.

ABSTRACT:

Background

Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native ?-helical structures and their self-assembly into nonnative intermolecular ?-sheets has been proposed to trigger amyloid fibril formation in Alzheimer's and Parkinson's diseases.

Methods

Here, we use a battery of biophysical techniques to elucidate the conformational conversion of native ?-helices into amyloid fibrils using an all-? FF domain as a model system.

Results

We show that under mild denaturing conditions at low pH this FF domain self-assembles into amyloid fibrils. Theoretical and experimental dissection of the secondary structure elements in this domain indicates that the helix 1 at the N-terminus has both the highest ?-helical and amyloid propensities, controlling the transition between soluble and aggregated states of the protein.

Conclusions

The data illustrates the overlap between the propensity to form native ?-helices and amyloid structures in protein segments.

Significance

The results presented contribute to explain why proteins cannot avoid the presence of aggregation-prone regions and indeed use stable ?-helices as a strategy to neutralize such potentially deleterious stretches.

SUBMITTER: Castillo V

PROVIDER: S-EPMC3591442 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.

Castillo Virginia V Chiti Fabrizio F Ventura Salvador S

PloS one 20130307 3

<h4>Background</h4>Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native α-helical structures and their self-assembly into nonnative intermolecular β-sheets has been proposed to trigger amyloid fibril formation in Alzheimer's and Parkinson's diseases.<h4>Methods</h4>Here, we use a battery of biophysical techniques to elucidate the conformational conversion of n ...[more]

PMID: 23505482

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Project description:In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state.Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with (11)C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A(+)) or negative (A(-)). (18)F-fluorodeoxyglucose ((18)F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N(+)) or negative (N(-)). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A(-)N(-) to A(+)N(-); A(-)N(-) to A(-)N(+) (suspected non-Alzheimer's pathology); A(+)N(-) to A(+)N(+); and A(-)N(+) to A(+)N(+). We also estimated two age-specific rates to dementia: A(+)N(+) to dementia and A(-)N(+) to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age.At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 [87%] were clinically normal and 537 [13%] had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17.2 vs 1.6 per 100 person-years) for the transition from A(-)N(-) to A(-)N(+), three-times higher (20.8 vs 6.1) for A(+)N(-) to A(+)N(+), and five-times higher (13.2 vs 2.6) for A(-)N(+) to A(+)N(+). The rate of transition was also increased at age 85 years compared with age 65 years for A(+)N(+) to dementia (7.0 vs 0.8) and for A(-)N(+) to dementia (1.7 vs 0.6). The one exception to an exponential increase with age was the transition rate from A(-)N(-) to A(+)N(-), which increased from 4.0 transitions per 100 person-years at age 65 years to 6.9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies.Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population.National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation.

Dataset Information

The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.

Background

Methods

Results

Conclusions

Significance

Publications

The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.

Similar Datasets

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