5usr

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Crystal structure of human NFS1-ISD11 in complex with E. coli acyl-carrier protein at 3.09 angstroms

Structural highlights

5usr is a 12 chain structure with sequence from Escherichia coli K-12 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.09Å
Ligands:8Q1, LLP
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LYRM4_HUMAN Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

LYRM4_HUMAN Required for nuclear and mitochondrial iron-sulfur protein biosynthesis.[1] [2]

Publication Abstract from PubMed

In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase. Unlike prokaryotic cysteine desulfurases, the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies. The different quaternary structure results in an incompletely formed substrate channel and solvent-exposed pyridoxal 5'-phosphate cofactor and provides a rationale for the allosteric activator function of FXN in eukaryotic systems. The structure also reveals the 4'-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe-S cluster biosynthesis, and clarifying how defects in Fe-S cluster assembly lead to diseases such as Friedreich's ataxia. Moreover, our results support a lock-and-key model in which LYR proteins associate with acyl-ACP as a mechanism for fatty acid biosynthesis to coordinate the expression, Fe-S cofactor maturation, and activity of the respiratory complexes.

Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.,Cory SA, Van Vranken JG, Brignole EJ, Patra S, Winge DR, Drennan CL, Rutter J, Barondeau DP Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5325-E5334. doi:, 10.1073/pnas.1702849114. Epub 2017 Jun 20. PMID:28634302[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
16 reviews cite this structure
Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.
Rouault et al. (2017)
15 more
53 other articles
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See Also

References

  1. ↑ Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007 Apr 15;16(8):929-41. Epub 2007 Mar 1. PMID:17331979 doi:http://dx.doi.org/ddm038
  2. ↑ Shi Y, Ghosh MC, Tong WH, Rouault TA. Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis. Hum Mol Genet. 2009 Aug 15;18(16):3014-25. doi: 10.1093/hmg/ddp239. Epub 2009 May, 18. PMID:19454487 doi:http://dx.doi.org/10.1093/hmg/ddp239
  3. ↑ Cory SA, Van Vranken JG, Brignole EJ, Patra S, Winge DR, Drennan CL, Rutter J, Barondeau DP. Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5325-E5334. doi:, 10.1073/pnas.1702849114. Epub 2017 Jun 20. PMID:28634302 doi:http://dx.doi.org/10.1073/pnas.1702849114

Contents


PDB ID 5usr

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