Structural basis of the iron storage function of frataxin from single-particle reconstruction of the iron-loaded oligomer
(2008) In Biochemistry 47(17). p.4948-4954- Abstract
- The mitochondrial protein frataxin plays a central role in mitochondrial iron homeostasis, and frataxin deficiency is responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1 in 40000 children. Here we present a single-particle reconstruction from cryoelectron microscopic images of iron-loaded 24-subunit oligomeric frataxin particles at 13 and 17 angstrom resolution. Computer-aided classification of particle images showed heterogeneity in particle size, which was hypothesized to result from gradual accumulation of iron within the core structure. Thus, two reconstructions were created from two classes of particles with iron cores of different sizes. The reconstructions show the iron core of frataxin for the... (More)
- The mitochondrial protein frataxin plays a central role in mitochondrial iron homeostasis, and frataxin deficiency is responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1 in 40000 children. Here we present a single-particle reconstruction from cryoelectron microscopic images of iron-loaded 24-subunit oligomeric frataxin particles at 13 and 17 angstrom resolution. Computer-aided classification of particle images showed heterogeneity in particle size, which was hypothesized to result from gradual accumulation of iron within the core structure. Thus, two reconstructions were created from two classes of particles with iron cores of different sizes. The reconstructions show the iron core of frataxin for the first time. Compared to the previous reconstruction of iron-free particles from negatively stained images, the higher resolution of the present reconstruction allowed a more reliable analysis of the overall three-dimensional structure of the 24-meric assembly. This was done after docking the X-ray structure of the frataxin trimer into the EM reconstruction. The structure revealed a close proximity of the suggested ferroxidation sites of different monomers to the site proposed to serve in iron nucleation and mineralization. The model also assigns a new role to the N-terminal helix of frataxin in controlling the channel at the 4-fold axis of the 24-subunit oligomer. The reconstructions show that, together with some common features, frataxin has several unique features which distinguish it from ferritin. These include the overall organization of the oligomers, the way they are stabilized, and the mechanisms of iron core nucleation. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1205605
- author
- Schagerlöf, Ulrika LU ; Elmlund, Hans LU ; Gakh, Oleksandr ; Nordlund, Gustav ; Hebert, Hans ; Lindahl, Martin LU ; Isaya, Grazia and Al-Karadaghi, Salam LU
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Biochemistry
- volume
- 47
- issue
- 17
- pages
- 4948 - 4954
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000255164700010
- scopus:42449093713
- ISSN
- 0006-2960
- DOI
- 10.1021/bi800052m
- language
- English
- LU publication?
- yes
- id
- 0f5d8922-685a-4901-899c-2a50b9f491e8 (old id 1205605)
- date added to LUP
- 2016-04-01 12:28:17
- date last changed
- 2022-01-27 05:32:08
@article{0f5d8922-685a-4901-899c-2a50b9f491e8,
abstract = {{The mitochondrial protein frataxin plays a central role in mitochondrial iron homeostasis, and frataxin deficiency is responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1 in 40000 children. Here we present a single-particle reconstruction from cryoelectron microscopic images of iron-loaded 24-subunit oligomeric frataxin particles at 13 and 17 angstrom resolution. Computer-aided classification of particle images showed heterogeneity in particle size, which was hypothesized to result from gradual accumulation of iron within the core structure. Thus, two reconstructions were created from two classes of particles with iron cores of different sizes. The reconstructions show the iron core of frataxin for the first time. Compared to the previous reconstruction of iron-free particles from negatively stained images, the higher resolution of the present reconstruction allowed a more reliable analysis of the overall three-dimensional structure of the 24-meric assembly. This was done after docking the X-ray structure of the frataxin trimer into the EM reconstruction. The structure revealed a close proximity of the suggested ferroxidation sites of different monomers to the site proposed to serve in iron nucleation and mineralization. The model also assigns a new role to the N-terminal helix of frataxin in controlling the channel at the 4-fold axis of the 24-subunit oligomer. The reconstructions show that, together with some common features, frataxin has several unique features which distinguish it from ferritin. These include the overall organization of the oligomers, the way they are stabilized, and the mechanisms of iron core nucleation.}},
author = {{Schagerlöf, Ulrika and Elmlund, Hans and Gakh, Oleksandr and Nordlund, Gustav and Hebert, Hans and Lindahl, Martin and Isaya, Grazia and Al-Karadaghi, Salam}},
issn = {{0006-2960}},
language = {{eng}},
number = {{17}},
pages = {{4948--4954}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Biochemistry}},
title = {{Structural basis of the iron storage function of frataxin from single-particle reconstruction of the iron-loaded oligomer}},
url = {{http://dx.doi.org/10.1021/bi800052m}},
doi = {{10.1021/bi800052m}},
volume = {{47}},
year = {{2008}},
}