Mapping the structural transition in an amyloidogenic apolipoprotein A-I
(2007) In Biochemistry 46(34). p.9-9693- Abstract
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143-9149] indicate that Gly26 in the native apoprotein separates a preceding beta-strand structure (residues... (More)
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143-9149] indicate that Gly26 in the native apoprotein separates a preceding beta-strand structure (residues 20-25) from a downstream largely alpha-helical region. The current study demonstrates that the G26R variant promotes a structural transition of positions 27-56 to a mixture of coil and beta-strand secondary structure. Microscopy and staining by amyloidophilic dyes suggest that this alteration extends throughout the protein within 1 week of incubation in vitro, leading to insoluble aggregates of distinct morphology. The severe consequences of the Iowa mutation likely arise from the combination of losing the contribution of the native Gly residue in terminating beta-strand propagation and the promotion of beta-structure when an Arg is introduced adjacent to the succeeding residue of identical charge and size, Arg27.
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- author
- Lagerstedt, Jens O LU ; Cavigiolio, Giorgio ; Roberts, Linda M ; Hong, Hyun-Seok ; Jin, Lee-Way ; Fitzgerald, Paul G ; Oda, Michael N. and Voss, John C LU
- publishing date
- 2007-08-28
- type
- Contribution to journal
- publication status
- published
- keywords
- Apolipoprotein A-I, Circular Dichroism, Electron Spin Resonance Spectroscopy, Humans, Models, Molecular, Peptide Fragments, Phospholipids, Protein Conformation, Spectroscopy, Fourier Transform Infrared, Thiazoles, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- in
- Biochemistry
- volume
- 46
- issue
- 34
- pages
- 9 - 9693
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:17665932
- scopus:34548279287
- ISSN
- 0006-2960
- DOI
- 10.1021/bi7005493
- language
- English
- LU publication?
- no
- id
- 8a76dea7-a0d1-44fc-98c4-5e027e0cd5eb
- date added to LUP
- 2017-10-19 20:10:16
- date last changed
- 2024-01-14 08:07:09
@article{8a76dea7-a0d1-44fc-98c4-5e027e0cd5eb,
abstract = {{<p>The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143-9149] indicate that Gly26 in the native apoprotein separates a preceding beta-strand structure (residues 20-25) from a downstream largely alpha-helical region. The current study demonstrates that the G26R variant promotes a structural transition of positions 27-56 to a mixture of coil and beta-strand secondary structure. Microscopy and staining by amyloidophilic dyes suggest that this alteration extends throughout the protein within 1 week of incubation in vitro, leading to insoluble aggregates of distinct morphology. The severe consequences of the Iowa mutation likely arise from the combination of losing the contribution of the native Gly residue in terminating beta-strand propagation and the promotion of beta-structure when an Arg is introduced adjacent to the succeeding residue of identical charge and size, Arg27.</p>}},
author = {{Lagerstedt, Jens O and Cavigiolio, Giorgio and Roberts, Linda M and Hong, Hyun-Seok and Jin, Lee-Way and Fitzgerald, Paul G and Oda, Michael N. and Voss, John C}},
issn = {{0006-2960}},
keywords = {{Apolipoprotein A-I; Circular Dichroism; Electron Spin Resonance Spectroscopy; Humans; Models, Molecular; Peptide Fragments; Phospholipids; Protein Conformation; Spectroscopy, Fourier Transform Infrared; Thiazoles; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't}},
language = {{eng}},
month = {{08}},
number = {{34}},
pages = {{9--9693}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Biochemistry}},
title = {{Mapping the structural transition in an amyloidogenic apolipoprotein A-I}},
url = {{http://dx.doi.org/10.1021/bi7005493}},
doi = {{10.1021/bi7005493}},
volume = {{46}},
year = {{2007}},
}