TY  - JOUR
A1  - Friemel, Martin
A1  - Marelja, Zvonimir
A1  - Li, Kuanyu
A1  - Leimkühler, Silke
T1  - The N-Terminus of Iron-Sulfur Cluster Assembly Factor ISD11 Is Crucial for Subcellular Targeting and Interaction with L-Cysteine Desulfurase NFS1
JF  - Biochemistry
N2  - Assembly of iron sulfur (FeS) clusters is an important process in living cells. The initial sulfur mobilization step for FeS cluster biosynthesis is catalyzed by L-cysteine desulfurase NFS1, a reaction that is localized in mitochondria in humans. In humans, the function of NFS1 depends on the ISD11 protein, which is required to stabilize its structure. The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for FeS cluster formation. It has been suggested that the role of ISD11 is not restricted to its role in stabilizing the structure of NFS1, because studies of single-amino acid variants of ISD11 additionally demonstrated its importance for the correct assembly of the quaternary complex. In this study, we are focusing on the N-terminal region of ISD11 to determine the role of N-terminal amino acids in the formation of the complex with NFS1 and to reveal the mitochondria) targeting sequence for subcellular localization. Our in vitro studies with the purified proteins and in vivo studies in a cellular system show that the first 10 N-terminal amino acids of ISD11 are indispensable for the activity of NFS1 and especially the conserved "LYR" motif is essential for the role of ISD11 in forming a stable and active complex with NFS1.
Y1  - 2017
U6  - https://doi.org/10.1021/acs.biochem.6b01239
SN  - 0006-2960
VL  - 56
SP  - 1797
EP  - 1808
PB  - American Chemical Society
CY  - Washington
ER  - 
TY  - JOUR
A1  - Xia, Haiyan
A1  - Cao, Yun
A1  - Dai, Xiaoman
A1  - Marelja, Zvonimir
A1  - Zhou, Di
A1  - Mo, Ran
A1  - Al-Mahdawi, Sahar
A1  - Pook, Mark A.
A1  - Leimkühler, Silke
A1  - Rouault, Tracey A.
A1  - Li, Kuanyu
T1  - Novel Frataxin Isoforms May Contribute to the Pathological Mechanism of
 Friedreich Ataxia
JF  - PLOS ONE
N2  - Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum-specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA.
Y1  - 2012
U6  - https://doi.org/10.1371/journal.pone.0047847
SN  - 1932-6203
VL  - 7
IS  - 10
PB  - PUBLIC LIBRARY SCIENCE
CY  - SAN FRANCISCO
ER  -