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 "slug": "high-potential-iron-sulphur-protein",
 "title": "High potential iron-sulphur protein",
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 "excerpt": "High potential iron-sulphur protein (HiPIP), small bacterial electron-carrier protein with a 4Fe-4S cluster using the 3+/2+ redox couple at +50 to +450 mV, distinct from ferredoxins.",
 "snippet": "High potential iron-sulphur protein (HiPIP), small bacterial electron-carrier protein with a 4Fe-4S cluster using the 3+/2+ redox couple at +50 to +450 mV, distinct from ferredoxins.",
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 "markdown": "# High potential iron-sulphur protein\n\n**High potential iron-sulfur protein** (HiPIP) is a small soluble electron-transfer protein of photosynthetic bacteria that carries a single [4Fe-4S] iron-sulfur cluster and uses the unusually positive [Fe\\(_{4}\\)S\\(_{4}\\)]\\(^{3+/2+}\\) redox couple, giving reduction potentials in the range of +50 to +450 mV.<sup>[1](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)</sup> HiPIPs are found mainly in purple photosynthetic bacteria, where they shuttle electrons between the cytochrome bc\\(_{1}\\) complex and the photosynthetic reaction center.<sup>[1](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)</sup>\n\n| Key fact | Detail |\n|---|---|\n| Size and fold | Small soluble protein of about 10 kDa and 50–100 amino acid residues, with no extensive secondary structure; folding is driven by the cluster<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup><sup> • </sup><sup>[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)</sup> |\n| Cofactor | One Fe\\(_{4}\\)S\\(_{4}\\) cubane cluster at the molecular center, coordinated by four cysteine residues<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup><sup> • </sup><sup>[4](https://pubs.acs.org/doi/10.1021/acs.jpcb.8b07614)</sup> |\n| Redox couple | [Fe\\(_{4}\\)S\\(_{4}\\)]\\(^{3+/2+}\\), with midpoint potentials from +50 to +450 mV; the reduced form is the resting state and is stable in air<sup>[1](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)</sup><sup> • </sup><sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> |\n| Function | Electron donor to the photosynthetic reaction center, re-reducing the special pair of chlorophyll molecules; also an electron acceptor for sulfide dehydrogenase and thiosulfate dehydrogenase in purple sulfur bacteria<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup><sup> • </sup><sup>[1](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)</sup> |\n| Record structure | HiPIP from *Thermochromatium tepidum* solved at 0.48 Å resolution (2016), one of the highest-resolution protein crystal structures reported, enabling charge-density analysis of the cluster<sup>[5](https://www.nature.com/articles/nature18001)</sup> |\n| Contrast with ferredoxin | Ferredoxins carry the same cluster but use the [Fe\\(_{4}\\)S\\(_{4}\\)]\\(^{2+/1+}\\) couple at −100 to −645 mV; the two transitions are separated by about 1 V<sup>[6](https://pubmed.ncbi.nlm.nih.gov/41891427/)</sup> |\n| Highest potential | The HiPIP of *Rhodopila globiformis* has a redox potential of about 450 mV, 100 mV higher than any other known iron-sulfur protein<sup>[7](https://pubmed.ncbi.nlm.nih.gov/8215406/)</sup> |\n\n## Structure and cofactor\n\nHiPIP is a compact single-domain protein of roughly 10 kDa whose defining feature is one Fe\\(_{4}\\)S\\(_{4}\\) cluster at the molecular center.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> The cluster is a distorted cube, describable as a tetrahedron of four iron atoms interpenetrating a larger tetrahedron of four inorganic sulfide ions, with each iron also bound by the thiolate sulfur of a cysteine residue.<sup>[8](https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/iron-sulfur-protein)</sup><sup> • </sup><sup>[4](https://pubs.acs.org/doi/10.1021/acs.jpcb.8b07614)</sup> Despite their small size, HiPIPs are difficult targets for NMR because both oxidation states of the cluster are paramagnetic at room temperature, which broadens and shifts resonances near the cluster-binding cysteines.<sup>[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)</sup>\n\nThe protein environment around the cluster is distinctive. Aromatic residues, typically a tryptophan and a tyrosine, tryptophan, or phenylalanine at conserved positions near the last cluster-bound cysteine, provide a hydrophobic shield that is thought to stabilize the cluster and support the very high potential of the 3+/2+ pair.<sup>[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)</sup> In bacteria, HiPIPs are assembled in the cytoplasm and exported to the periplasm as folded holoproteins through the TAT translocation system.<sup>[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)</sup>\n\n## Electron-transfer function\n\nIn the photosynthetic chain, HiPIP supplies an electron from the cytochrome bc\\(_{1}\\) complex to the photosynthetic reaction center, re-reducing the special pair of chlorophyll molecules after photoexcitation.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> In some phototrophic proteobacteria this soluble-mediator role is traditionally assigned to cytochrome c\\(_{2}\\); a survey of electron-carrier distributions concluded that HiPIP is likely the carrier of choice in the purple sulfur bacteria of the families Chromatiaceae and Ectothiorhodospiraceae, whereas most purple nonsulfur bacteria use cytochrome c\\(_{2}\\).<sup>[9](https://pubmed.ncbi.nlm.nih.gov/14562962/)</sup>\n\nHiPIPs also participate in sulfur metabolism, acting as electron acceptors for sulfide dehydrogenase and [thiosulfate dehydrogenase](https://www.edgepedia.org/thiosulfate-dehydrogenase) in purple sulfur bacteria, and serve as electron donors to the oxygen reductases of organisms such as *Rhodoferax fermentans* relatives.<sup>[1](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)</sup> Their physiological role as reaction-center donors was demonstrated experimentally only in 1995, after three decades of biophysical characterization.<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC552902/)</sup>\n\n## Why the potential is high\n\nThe central puzzle of the HiPIP family is that ferredoxins contain the identical [Fe\\(_{4}\\)S\\(_{4}\\)(Cys)\\(_{4}\\)] cofactor yet operate at low potential. Ferredoxins use the 2−/3− transition at −100 to −645 mV, while HiPIPs use the 1−/2− transition, written [Fe\\(_{4}\\)S\\(_{4}\\)]\\(^{2+/3+}\\), at +100 to +450 mV versus the normal hydrogen electrode.<sup>[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC2785490/)</sup> Continuum electrostatics calculations indicate that moving the cluster from water into the protein interior lowers the potential of both transitions, but penalizes the low-potential transition more because its redox states carry higher charge; the separation between the two transitions grows to about 1 V, and protein background charges such as peptide-bond dipoles then tune only one transition into the physiological window while pushing the other out of the biologically accessible range.<sup>[6](https://pubmed.ncbi.nlm.nih.gov/41891427/)</sup>\n\nStructural explanations point in the same direction: the differences in oxidation level used by HiPIPs, compared with low-potential ferredoxins, are attributed mainly to local amide dipoles, the more hydrophobic environment of the cluster, and fewer hydrogen bonds.<sup>[12](https://www.sciencedirect.com/science/article/pii/S0898883808600288)</sup> The backbone fold sets the approximate range of the potential, and specific sequence patterns fine-tune the value.<sup>[8](https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/iron-sulfur-protein)</sup> At the top of the range, the *Rhodopila globiformis* HiPIP reaches about 450 mV.<sup>[7](https://pubmed.ncbi.nlm.nih.gov/8215406/)</sup>\n\n## Ultra-high-resolution structural studies\n\nHiPIP from the thermophilic purple bacterium *Thermochromatium tepidum* has produced two landmark crystal structures. In 2016, its structure was refined at 0.48 Å resolution, one of the highest resolutions reported for any protein, which allowed a charge-density analysis visualizing the distributions of valence electrons around the iron and sulfur atoms of the cluster.<sup>[5](https://www.nature.com/articles/nature18001)</sup> In 2017, the oxidized state was determined at 0.8 Å and compared with the reduced form.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup>\n\nThe comparison showed no global conformational change on oxidation: the main-chain root-mean-square deviation was 0.039 Å, while the cluster itself deviated by 0.020 Å, well above the refinement uncertainty of 0.003 Å.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> The cluster contracts on oxidation, with intra-subcluster Fe-S bonds shortening and the Fe-(Cys-S\\(_{\\gamma}\\)) bonds of all four irons also decreasing, changes similar to those predicted by theoretical calculation for a model compound.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> Most distances between cluster sulfur atoms and the surrounding peptide lengthen on oxidation, showing that the protein envelope does not follow the cluster's contraction.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup> The redox midpoint potential of the *T. tepidum* protein is approximately +300 mV, so the reduced form is the resting state under normal atmospheric conditions.<sup>[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)</sup>\n\n## Distribution and relatives\n\nHiPIPs occur in photosynthetic and nonphotosynthetic proteobacteria and in members of the Flexibacter, Bacteroides, and [Cytophaga](https://www.edgepedia.org/cytophaga) group.<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC552902/)</sup> Sequence comparisons identify a minimum of three sequence categories, which roughly follow the three families of phototrophic proteobacteria.<sup>[9](https://pubmed.ncbi.nlm.nih.gov/14562962/)</sup> The smallest known HiPIP is PioC from *Rhodopseudomonas palustris* TIE-1, a 54-residue protein with a potential of +450 mV that is proposed to connect the [iron oxidase](https://www.edgepedia.org/iron-oxidase) PioA to the reaction center during photoferrotrophic growth.<sup>[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)</sup> A soluble high-potential-type iron-sulfur protein from beef heart mitochondria was shown in 1978 to be aconitase, which shares the light-absorption and EPR characteristics of the HiPIP type.<sup>[13](https://www.sciencedirect.com/science/article/pii/S0021925817408490)</sup>\n\n## References\n\n1. [Purification and properties of high-potential iron-sulfur proteins, Methods in Enzymology 243 (1994)](https://www.sciencedirect.com/science/chapter/bookseries/abs/pii/0076687994430330)\n2. [Ohno H, Takeda K, Niwa S, et al. (2017). Crystallographic characterization of the high-potential iron-sulfur protein in the oxidized state at 0.8 Å resolution. PLoS ONE 12(5): e0178183](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178183)\n3. [Trindade IB, et al. (2020). 1H, 13C and 15N assignment of the paramagnetic HiPIP PioC from Rhodopseudomonas palustris TIE-1. Biomol NMR Assign 14(2):211–215](https://pmc.ncbi.nlm.nih.gov/articles/PMC7462912/)\n4. [Mechanical Unfolding Pathway of the High-Potential Iron–Sulfur Protein Revealed by Single-Molecule Atomic Force Microscopy. J Phys Chem B 122(40):9340–9349 (2018)](https://pubs.acs.org/doi/10.1021/acs.jpcb.8b07614)\n5. [Hirano Y, Takeda K, Miki K (2016). Charge-density analysis of an iron–sulfur protein at an ultra-high resolution of 0.48 Å. Nature 534:281–284](https://www.nature.com/articles/nature18001)\n6. [Fundamental Electrostatics Explains Why Ferredoxin- and HiPIP-Type Proteins Favor Different Redox Transitions in [4Fe-4S]-Cys4 Clusters](https://pubmed.ncbi.nlm.nih.gov/41891427/)\n7. [Ambler RP, Meyer TE, Kamen MD (1993). Amino acid sequence of a high redox potential ferredoxin (HiPIP) from Rhodopila globiformis. Arch Biochem Biophys 306(1):215–222](https://pubmed.ncbi.nlm.nih.gov/8215406/)\n8. [Iron-Sulfur Protein, ScienceDirect Topics overview](https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/iron-sulfur-protein)\n9. [Amino acid sequences and distribution of high-potential iron-sulfur proteins that donate electrons to the photosynthetic reaction center in phototropic proteobacteria](https://pubmed.ncbi.nlm.nih.gov/14562962/)\n10. [Study of the high-potential iron sulfur protein in Halorhodospira halophila confirms that it is distinct from cytochrome c as electron carrier](https://pmc.ncbi.nlm.nih.gov/articles/PMC552902/)\n11. [Insight into Environmental Effects on Bonding and Redox Properties of [4Fe-4S] Clusters in Proteins](https://pmc.ncbi.nlm.nih.gov/articles/PMC2785490/)\n12. [Structure-Function Correlations in High-Potential IRON Proteins. Advances in Inorganic Chemistry 45:313–350 (1998)](https://www.sciencedirect.com/science/article/pii/S0898883808600288)\n13. [The soluble \"high potential\" type iron-sulfur protein from mitochondria is aconitase. J Biol Chem 253(8):2514–2517 (1978)](https://www.sciencedirect.com/science/article/pii/S0021925817408490)\n\n---\n*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Protein families and complexes › Electron transport and redox protein families*\n\n*Initially written Oct 21, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n",
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