Mitochondrial complex III Rieske Fe-S protein processing and assembly

Figures & data

Figure 1. UQCRFS1 pathway from synthesis of the precursor in the cytoplasm, transport into the mitochondrial matrix through the TOM/TIM23 import system, incorporation of the [2Fe-2S] clusters in the matrix and translocation to pre-cIII₂ in the inner membrane (IM). According to our model, the N-terminal MTS is cleaved off in situ by the UQCRC1+UQCRC2 MPP activity. See main text for more details.

Figure 2. Graphic alignment of the Rieske protein precursors from yeast (S. cerevisiae), fruit fly (D. melanogaster), chicken (G. gallus) and mammals (bovine, mouse and human). Numbers indicate relevant residue positions. The two yeast cleavage sites, at positions 22 and 30 are indicated with arrows. The main cleavage site, conserved in all organisms is indicated with the big arrow. Different color MTS indicates the lack of homology of these sequences, while the homology in the mature protein sequences in very high.

Figure 3. Structures of full complex III dimer (cIII₂) and of isolated UQCRFS1 (of only one of the monomers), from bovine (PDB ID: 1BGY) and chicken (PDB ID: 3H1J). The arrows indicate the presence of the UQCRFS1 fragments in the cavity between UQCRC1 and UQCRC2. Images were generated with MacPyMol.

Table 1. UQCRFS1 MTS sequences found in the published cIII₂ structures

PDB ID	Reference	UQCRFS1 positions found
BOVINE STRUCTURES UQCRFS1 MTS: Positions 1 to 78
1BGY, 1BE3	[1]	From 48 to 78
1L0L, 1L0N, 1NTK, 1NTM, 1NTZ, 1NU1, 1SQB, 1SQP, 1SQQ, 1SQV, 1SQX, 2FYU	[53–56]	From 1 to 57
1PP9, 1PPJ, 2A06	[57]	From 32 to 42 and from 48 to 78
1QCR	[58]	From 21 to 48
4D6U, 4D6T	[59]	Monomer 1: From 50 to 56 and from 64 to 77 Monomer 2: From 62 to 63 and from 65 to 78
5KLV	[60]	From 20 to 27; from 44 to 61 and from 63 to 70
5NMI	[61]	From 49 to 78
CHICKEN STRUCTURES UQCRFS1 MTS: Positions 1 to 76
1BCC, 2BCC, 3BCC	[3]	—-
3H1L, 3H1H, 3H1I, 3H1J, 3H1K	[62]	From 45 to 63
3CWB, 4U3F	[63,64]	From 46 to 75
3TGU	[65]	From 2 to 8 and from 46 to 75
3L70, 3L71, 3L72, 3L73, 3L74	[66]	From 45 to 75
HUMAN STRUCTURE UQCRFS1 MTS: Positions 1 to 78
5XTE	[5]	From 1 to 57

Iwata S, Lee JW, Okada K, et al. Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science. 1998;281:64–71. doi:10.1126/science.281.5373.64. PMID:9651245

 PubMed Web of Science ®Google Scholar

Huang LS, Cobessi D, Tung EY, et al. Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex: a new crystal structure reveals an altered intramolecular hydrogen-bonding pattern. J Mol Biol. 2005;351:573–597. doi:10.1016/j.jmb.2005.05.053. PMID:16024040

 PubMed Web of Science ®Google Scholar

Xia D, Yu CA, Kim H, et al. Crystal structure of the cytochrome bc1 complex from bovine heart mitochondria. Science. 1997;277:60–66. doi:10.1126/science.277.5322.60. PMID:9204897

 PubMed Web of Science ®Google Scholar

Capper MJ, O'Neill PM, Fisher N, et al. Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1. PNAS. 2015;112:755–760. doi:10.1073/pnas.1416611112. PMID:25564664

 PubMed Web of Science ®Google Scholar

Esser L, Zhou F, Zhou Y, et al. Hydrogen bonding to the substrate is not required for Rieske Iron-Sulfur Protein Docking to the Quinol Oxidation Site of Complex III. J Biol Chem. 2016;291:25019–25031. doi:10.1074/jbc.M116.744391. PMID:27758861

 PubMed Web of Science ®Google Scholar

McPhillie M, Zhou Y, El Bissati K, et al. New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Sci Rep. 2016;6:29179. doi:10.1038/srep29179. PMID:27412848

 PubMed Web of Science ®Google Scholar

Zhang Z, Huang L, Shulmeister VM, et al. Electron transfer by domain movement in cytochrome bc1. Nature. 1998;392:677–684. doi:10.1038/33612. PMID:9565029

 PubMed Web of Science ®Google Scholar

Berry EA, Huang LS, Lee DW, et al. Ascochlorin is a novel, specific inhibitor of the mitochondrial cytochrome bc1 complex. Biochim Biophys Acta. 2010;1797:360–370. doi:10.1016/j.bbabio.2009.12.003. PMID:20025846

 PubMed Web of Science ®Google Scholar

Crowley PJ, Berry EA, Cromartie T, et al. The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D. Bioorg Med Chem. 2008;16:10345–10355. doi:10.1016/j.bmc.2008.10.030. PMID:18996700

 PubMed Web of Science ®Google Scholar

Hao G-F, Yang, S.-G., Huang, W., et al. Rational design of highly potent and slow-binding cytochrome bc1 inhibitor as fungicide by computational substitution optimization. To be published 2015.

 Google Scholar

Hao GF, Wang F, Li H, et al. Computational discovery of picomolar Q(o) site inhibitors of cytochrome bc1 complex. J Am Chem Soc. 2012;134:11168–11176. doi:10.1021/ja3001908. PMID:22690928

 PubMed Web of Science ®Google Scholar

Huang L, Berry, E.A. Famoxadone and related inhibitors bind like methoxy acrylate inhibitors in the Qo site of the BC1 compl and fix the rieske iron-sulfur protein in a positio close to but distinct from that seen with stigmatellin and other "distal" Qo inhibitors. To be published 2010.

 Google Scholar

Guo R, Zong S, Wu M, et al. Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. Cell. 2017;170:1247–1257, e12.

 PubMed Web of Science ®Google Scholar