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Stepwise unfolding of human β-microglobulin into a disordered amyloidogenic precursor at low pH.

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Title: Stepwise unfolding of human β-microglobulin into a disordered amyloidogenic precursor at low pH.
Authors: Narang, Dominic1, Singh, Anubhuti2, Mukhopadhyay, Samrat mukhopadhyay@iisermohali.ac.in
Source: European Biophysics Journal. Jan2017, Vol. 46 Issue 1, p65-76. 12p.
Subjects: Microglobulins, Protein folding, Amyloid beta-protein, Protein precursors, Amyloidosis, Dialysis (Chemistry)
Abstract: Amyloid fibril formation by human β-microglobulin (βm) is associated with dialysis-related amyloidosis. In order to understand the mechanism of protein misfolding, it is important to characterize the nature and properties of various intermediates formed during protein unfolding. In this work, we studied the effect of pH change on the unfolding of βm using a range of spectroscopic readouts. In order to investigate the local structural changes, we created single tryptophan (W60 and W95) mutants of βm. The equilibrium results suggested that in the acid-unfolded state of βm at pH 2.5, the W60 residue attains non-native local structure whereas the W95 residue becomes more exposed. Our stopped-flow kinetic data revealed that βm undergoes unfolding in a stepwise manner. Initial unfolding of βm involves non-uniform protein expansion with the unpacking of tertiary structure and significant core solvation while maintaining a native-like structure around residue W95. The resolved-phase of unfolding exhibits a timescale of ~500 ms that describes the transition from the native-like swollen intermediate to an acid-induced disordered state. Taken together, our results demonstrate that βm has a complex pH-induced unfolding mechanism yielding a disordered amyloidogenic precursor comprising both exposed and buried segments. [ABSTRACT FROM AUTHOR]
Copyright of European Biophysics Journal is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Stepwise unfolding of human β-microglobulin into a disordered amyloidogenic precursor at low pH.
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  Data: <searchLink fieldCode="AR" term="%22Narang%2C+Dominic%22">Narang, Dominic</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Singh%2C+Anubhuti%22">Singh, Anubhuti</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Mukhopadhyay%2C+Samrat%22">Mukhopadhyay, Samrat</searchLink><i> mukhopadhyay@iisermohali.ac.in</i>
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  Data: <searchLink fieldCode="JN" term="%22European+Biophysics+Journal%22">European Biophysics Journal</searchLink>. Jan2017, Vol. 46 Issue 1, p65-76. 12p.
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  Data: <searchLink fieldCode="DE" term="%22Microglobulins%22">Microglobulins</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+folding%22">Protein folding</searchLink><br /><searchLink fieldCode="DE" term="%22Amyloid+beta-protein%22">Amyloid beta-protein</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+precursors%22">Protein precursors</searchLink><br /><searchLink fieldCode="DE" term="%22Amyloidosis%22">Amyloidosis</searchLink><br /><searchLink fieldCode="DE" term="%22Dialysis+%28Chemistry%29%22">Dialysis (Chemistry)</searchLink>
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  Data: Amyloid fibril formation by human β-microglobulin (βm) is associated with dialysis-related amyloidosis. In order to understand the mechanism of protein misfolding, it is important to characterize the nature and properties of various intermediates formed during protein unfolding. In this work, we studied the effect of pH change on the unfolding of βm using a range of spectroscopic readouts. In order to investigate the local structural changes, we created single tryptophan (W60 and W95) mutants of βm. The equilibrium results suggested that in the acid-unfolded state of βm at pH 2.5, the W60 residue attains non-native local structure whereas the W95 residue becomes more exposed. Our stopped-flow kinetic data revealed that βm undergoes unfolding in a stepwise manner. Initial unfolding of βm involves non-uniform protein expansion with the unpacking of tertiary structure and significant core solvation while maintaining a native-like structure around residue W95. The resolved-phase of unfolding exhibits a timescale of ~500 ms that describes the transition from the native-like swollen intermediate to an acid-induced disordered state. Taken together, our results demonstrate that βm has a complex pH-induced unfolding mechanism yielding a disordered amyloidogenic precursor comprising both exposed and buried segments. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of European Biophysics Journal is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Text: English
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              Text: Jan2017
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