Archaerhodopsin Explained

Archaerhodopsin proteins are a family of retinal-containing photoreceptors found in the archaea genera Halobacterium and Halorubrum. Like the homologous bacteriorhodopsin (bR) protein, archaerhodopsins harvest energy from sunlight to pump H+ ions out of the cell, establishing a proton motive force that is used for ATP synthesis. They have some structural similarities to the mammalian G protein-coupled receptor protein rhodopsin, but are not true homologs.

Archaerhodopsins differ from bR in that the claret membrane, in which they are expressed, includes bacterioruberin, a second chromophore thought to protect against photobleaching. Also, bR lacks the omega loop structure observed at the N-terminus of the structures of several archaerhodopsins.

Mutants of Archaerhodopsin-3 (AR3) are used as tools in optogenetics for neuroscience research.[1]

Etymology

The term archaerhodopsin is a portmanteau of archaea (the domain in which the proteins are found) and rhodopsin (a photoreceptor responsible for vision in the mammalian eye).[2]

archaea from Ancient Greek ἀρχαῖα (arkhaîa, "ancient"), the plural and neuter form of ἀρχαῖος (arkhaîos, "ancient").[3]

rhodopsin from Ancient Greek ῥόδον (rhódon, "rose"), because of its pinkish color, and ὄψις (ópsis, "sight").[4]

History

In the 1960s, a light driven proton pump was discovered in Halobacterium salinarum, and called Bacteriorhodopsin. Over the following years, there were various studies of the membrane of H. salinarum to determine the mechanism of these light-driven proton pumps.

In 1988, another Manabu Yoshida's group at Osaka University reported a novel light-sensitive proton pump from a strain of Halobacterium which they termed Archaerhodopsin.[2] A year later, the same group reported isolating the gene that encodes Archaerhodopsin.[5]

Family members

Seven members of the archaerhodopsin family have been identified to date.

Name Abbr. Organism GenBank UniProt PDB Ref.
Archaerhodopsin-1 AR1 Halobacterium sp. Aus-1 J05165 P69052 1UAZ
Archaerhodopsin-2 AR2 Halobacterium sp. Aus-2 S56354 P29563 3WQJ [6]
Archaerhodopsin-3 AR3 or Arch Halorubrum sodomense GU045593 P96787 6S6C [7]
Archaerhodopsin-4 AR4 Halobacterium sp. xz515 AF306937 [8]
Archaerhodopsin-BD1 AR-BD1 or HxAR Halorubrum xinjiangense AY510709 Q6R5N7 [9]
Archaerhodopsin-He HeAr Halorubrum ejinorense LC073751 [10]
Archaerhodopsin-TP009 AR-TP009 Halorubrum sp. TP009 [11]

AR1 and AR2

Archaerhodopsin 1 and 2 (AR1 and AR2) were the first archaerhodopsins to be identified and are expressed by Halobacterium sp. Aus-1 and Aus-2 respectively. Both species were first isolated in Western Australia in the late 1980s.[2] [6] [12] The crystal structures of both proteins were solved by Kunio Ihara, Tsutomo Kouyama and co-workers at Nagoya University, together with collaborators at the Spring-8 synchrotron.[13]

AR3/Arch

AR3 is expressed by Halorubrum sodomense.[7] The organism was first identified in the Dead Sea in 1980 and requires a higher concentration of Mg2+ ions for growth than related halophiles.[14] The aop3 gene was cloned by Ihara and colleagues at Nagoya University in 1999 and the protein was found to share 59% sequence identity with bacteriorhodopsin.[7] The crystal structure of AR3 was solved by Anthony Watts at Oxford University and Isabel Moraes at the National Physical Laboratory, together with collaborators at Diamond Light Source.[15]

Mutants of Archaerhodopsin-3 (AR3) are widely used as tools in optogenetics for neuroscience research.[1]

AR3 has recently been introduced as a fluorescent voltage sensor.[16]

AR4

AR4 is expressed in Halobacterium species xz 515. The organism was first identified in a salt lake in Tibet.[8] [17] The gene encoding it was identified by H. Wang and colleagues in 2000.[18] In most bacteriorhodopsin homologs, H+ release to the extracellular medium takes place before a replacement ion is taken up from the cytosolic side of the membrane. Under the acidic conditions found in the organism's native habitat, the order of these stages in the AR4 photocycle is reversed.[19]

AR-BD1

AR-BD1 (also known as HxAR) is expressed by Halorubrum xinjiangense.[9] The organism was first isolated from Xiao-Er-Kule Lake in Xinjiang, China.[20]

HeAr

HeAR is expressed by Halorubrum ejinorense.[10] The organism was first isolated from Lake Ejinor in Inner Mongolia, China.[21]

AR-TP009/ArchT

AR-TP009 is expressed by Halorubrum sp. TP009. Its ability to act as a neural silencer has been investigated in mouse cortical pyramidal neurons.[11]

General features

Occurrence

Like other members of the microbial rhodopsin family, archaerhodopsins are expressed in specialised, protein-rich domains of the cell surface membrane, commonly called the claret membrane. In addition to ether lipids, the claret membrane contains bacterioruberin, (a 50-carbon carotenoid pigment) which is thought to protect against photobleaching. Atomic force microscope images of the claret membranes of several archaerhodopsins, show that the proteins are trimeric and are arranged in a hexagonal lattice.[22] Bacterioruberin has also been implicated in oligomerisation and may facilitate protein-protein interactions in the native membrane.[23] [24]

Function

Archaerhodopsins are active transporters, using the energy from sunlight to pump H+ ions out of the cell to generate a proton motive force that is used for ATP synthesis. Removal of the retinal cofactor (e.g. by treatment with hydroxylamine) abolishes the transporter function and dramatically alters the absorption spectra of the proteins. The proton pumping ability of AR3 has been demonstrated in recombinant E. coli cells[25] and of AR4 in liposomes.[19]

In the resting or ground state of archaerhodopsin, the bound retinal is in the all-trans form, but on absorption of a photon of light, it isomerizes to 13-cis. The protein surrounding the chromophore reacts to the change of shape and undergoes an ordered sequence of conformational changes, which are collectively known as the photocycle. These changes alter the polarity of the local environment surrounding titratable amino acid side chains inside the protein, enabling H+ to be pumped from the cytoplasm to the extracellular side of the membrane. The intermediate states of the photocycle may be identified by their absorption maxima.[19] [26]

Structures

Crystal structures of the resting or ground states of AR1 (3.4 Å resolution), AR2 (1.8 Å resolution) and AR3 (1.07 and 1.3 Å) have been deposited in the Protein Data Bank.[13] [27] [15] Proteins possess seven transmembrane α-helices and a two-stranded extracellular-facing β-sheet. Retinal is covalently bonded via Schiff base to a lysine residue on helix G.[13] [15] The conserved DLLxDGR sequence, close to the extracellular-facing N-terminus of both proteins, forms a tightly curved omega loop that has been implicated in bacterioruberin binding.[23] The cleavage of the first 6 amino acids and the conversion of Gln7 to a pyroglutamate (PCA) residue was also observed in AR3, as previously reported for bacteriorhodopsin.[15]

Use in research

Archaerhodopsins drive the hyperpolarization of the cell membrane by secreting protons in presence of light, thereby inhibiting action potential firing of neurons.[28] This process is associated with an increase in extracellular H+ (i.e. decreased pH linked to the activity of these proteins. These characteristics allow for Archaerhodopsins to be commonly used tools for optogenetic studies as they behave as transmission inhibition factors in presence of light.[29] When expressed within intracellular membranes, the proton pump activity increases the cytosolic pH, this functionality can be used for optogenetic acidification of lysosomes and synaptic vesicles when targeted to these organelles.[30]

Notes and References

  1. Flytzanis NC, Bedbrook CN, Chiu H, Engqvist MK, Xiao C, Chan KY, Sternberg PW, Arnold FH, Gradinaru V . 2014 . Archaerhodopsin variants with enhanced voltage-sensitive fluorescence in mammalian and Caenorhabditis elegans neurons . Nature Communications . 5 . 4894 . 10.1038/ncomms5894 . 4166526 . 25222271 . 2014NatCo...5.4894F .
  2. Mukohata Y, Sugiyama Y, Ihara K, Yoshida M . An Australian halobacterium contains a novel proton pump retinal protein: archaerhodopsin . Biochemical and Biophysical Research Communications . 151 . 3 . 1339–45 . March 1988 . 2833260 . 10.1016/S0006-291X(88)80509-6.
  3. https://en.wiktionary.org/wiki/Archaea Archaea
  4. https://en.wiktionary.org/wiki/rhodopsin Rhodopsin
  5. Enzyme diversity in halophilic archaea. 8 April 2018. Microbiología. Oren. A. 1994. 10. 3. 217–228. 7873098. https://web.archive.org/web/20120704045912/http://www.semicrobiologia.org/info/revista_hist/10_3.pdf. 4 July 2012. dead.
  6. Uegaki K, Sugiyama Y, Mukohata Y . Archaerhodopsin-2, from Halobacterium sp. aus-2 further reveals essential amino acid residues for light-driven proton pumps . Archives of Biochemistry and Biophysics . 286 . 1 . 107–10 . April 1991 . 1654776 . 10.1016/0003-9861(91)90014-A.
  7. Ihara K, Umemura T, Katagiri I, Kitajima-Ihara T, Sugiyama Y, Kimura Y, Mukohata Y . Evolution of the archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation . Journal of Molecular Biology . 285 . 1 . 163–74 . January 1999 . 9878396 . 10.1006/jmbi.1998.2286 .
  8. Li Q, Sun Q, Zhao W, Wang H, Xu D . Newly isolated archaerhodopsin from a strain of Chinese halobacteria and its proton pumping behavior . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1466 . 1–2 . 260–6 . June 2000 . 10825447 . 10.1016/S0005-2736(00)00188-7.
  9. Geng X, Dai G, Chao L, Wen D, Kikukawa T, Iwasa T . 2019 . Two consecutive polar amino acids at the end of helix E are important for fast turnover of the archaerhodopsin photocycle . Photochemistry and Photobiology . 95 . 4 . 980–989 . 10.1111/php.13072 . 30548616 . 56484521 . free .
  10. Chaoluomeng, Dai G, Kikukawa T, Ihara K, Iwasa T . 2015 . Microbial Rhodopsins of Halorubrum Species Isolated From Ejinoor Salt Lake in Inner Mongolia of China . Photochem. Photobiol. Sci. . 14 . 11 . 1974–82 . 10.1039/c5pp00161g . 26328780 . free .
  11. Xue H, Chow BY, Zhou H, Klapoetke NC, Chuong A, Rajimehr R, Yang A, Baratta MV, Winkle J, Desimone R, Boyden ES . 2011 . A high-light sensitivity optical neural silencer: Development and application to optogenetic control of non-human primate cortex . Frontiers in Systems Neuroscience. 5 . 18 . 1–8 . 10.3389/fnsys.2011.00018. 21811444 . 3082132 . free .
  12. Sugiyama Y, Maeda M, Futai M, Mukuhata Y. 1989 . Isolation of a Gene That Encodes a New Retinal Protein, Archaerhodopsin, From Halobacterium Sp. Aus-1 . J. Biol. Chem. . 264 . 35 . 20859–62 . 10.1016/S0021-9258(19)30014-6 . 2592356 . free .
  13. Enami N, Yoshimura K, Murakami M, Okumura H, Ihara K, Kouyama T . 2006 . Crystal Structures of Archaerhodopsin-1 and -2: Common structural motif in archaeal light-driven proton pumps . J. Mol. Biol. . 358 . 3. 675–685 . 10.1016/j.jmb.2006.02.032 . 16540121.
  14. Oren A . 1983 . Halobacterium sodomense sp. nov. a Dead Sea Halobacterium with an extremely high magnesium requirement . International Journal of Systematic Bacteriology . 33 . 2 . 381–386. 10.1099/00207713-33-2-381 . free .
  15. Bada Juarez JF, Judge PJ, Adam S, Axford D, Vinals J, Birch J, Kwan TO, Hoi KK, Yen HY, Vial A, Milhiet PE, Robinson CV, Schapiro I, Moraes I, Watts A . 2021 . Structures of the archaerhodopsin 3 transporter reveal that disordering of internal water networks underpins receptor sensitization . Nature Communications . 12 . 1 . 629 . 10.1038/s41467-020-20596-0 . 7840839 . 33504778 . 2021NatCo..12..629B .
  16. Kralj JM, Douglass AD, Hochbaum DR, Maclaurin D, Cohen AE . Optical recording of action potentials in mammalian neurons using a microbial rhodopsin . Nature Methods . 9 . 1 . 90–5 . November 2011 . 22120467 . 3248630 . 10.1038/nmeth.1782 .
  17. Wang Y, Ma D, Zhao Y, Ming M, Wu J, Ding J . 2012 . Light-driven proton pumps of archaerhodopsin and bacteriorhodopsin & polymer-matrix composite materials of those functional proteins . Acta Polymerica Sinica . 12 . 7 . 698–713 . 10.3724/SP.J.1105.2012.12051 . free .
  18. Wang, S. Zhan, Q. Sun, D. Xu, W. Zhao, W. Huang, Q. Li., 2000. Primary structure of helix C to helix G of a new retinal protein in H.sp.xz515. Chin. Sci. Bull., 45: 1108-1113.
  19. Ming M, Lu M, Balashov SP, Ebrey TG, Li Q, Ding J . 2006 . pH Dependence of Light-Driven Proton Pumping by an Archaerhodopsin From Tibet: Comparison With Bacteriorhodopsin . Biophys. J. . 90 . 9 . 3322–32 . 10.1529/biophysj.105.076547. 1432102 . 16473896 . 2006BpJ....90.3322M .
  20. Feng J, Zhou PJ, Liu SJ . 2004 . Halorubrum xinjiangense sp. nov., a novel halophile isolated from saline lakes in China . International Journal of Systematic and Evolutionary Microbiology . 54 . 5. 1789–1791 . 10.1099/ijs.0.63209-0 . 15388744. free .
  21. Castillo AM, Gutiérrez MC, Kamekura M, Xue Y, Ma Y, Cowan DA, Jones BE, Grant WD, Ventosa A . 2007 . Halorubrum Ejinorense Sp. Nov., Isolated From Lake Ejinor, Inner Mongolia, China . International Journal of Systematic and Evolutionary Microbiology . 57 . 11 . 2538–2542 . 10.1099/ijs.0.65241-0 . 17978215. free .
  22. Tang L, Sun Q, Li Q, Huang Y, Wei Q, Zhang Y, Hu J, Zhang Z . 96378194 . 2001 . Imaging bacteriorhodopsinlike molecules of claretmembranes from Tibet halobacteria xz515 by atomic force microscope . Chinese Science Bulletin . 46 . 22. 1897–1900. 10.1007/BF02901167. 2001ChSBu..46.1897T .
  23. Yoshimura K, Kouyama T . 2008 . Structural Role of Bacterioruberin in the Trimeric Structure of Archaerhodopsin-2 . Journal of Molecular Biology . 375 . 5 . 1267–81 . 10.1016/j.jmb.2007.11.039 . 18082767.
  24. Chao S, Ding X, Cui H, Yang Y, Chen S, Watts A, Zhao X . 2018 . In Situ Study of the Function of Bacterioruberin in the Dual-Chromophore Photoreceptor Archaerhodopsin-4 . Angew. Chem. . 57 . 29 . 8937–8941 . 10.1002/anie.201803195 . 29781190 .
  25. Gunapathy S, Kratx S, Chen Q, Hellingwerf K, de Groot H, Rothschild K, de Grip W . 2019 . Redshifted and Near-infrared Active Analog Pigments Based upon Archaerhodopsin-3 . Photochemistry and Photobiology . 95 . 4. 959–968 . 10.1111/php.13093 . 6849744 . 30860604.
  26. Geng X, Dai G, Chao L, Wen D, Kikukawa T, Iwasa T . 2019 . Two Consecutive Polar Amino Acids at the End of Helix E are Important for Fast Turnover of the Archaerhodopsin Photocycle . Photochemistry and Photobiology . 95 . 4. 980–989 . 10.1111/php.13072 . 30548616. 56484521 . free .
  27. Kouyama T, Fujii R, Kanada S, Nakanishi T, Chan SK, Midori M . 2014 . Structure of archaerhodopsin-2 at 1.8 Å Resolution . Acta Crystallogr D . 70 . 10 . 2692–701 . 4188009 . 25286853 . 10.1107/S1399004714017313.
  28. Chow BY, Han X, Dobry AS, Qian X, Chuong AS, Li M, Henninger MA, Belfort GM, Lin Y, Monahan PE, Boyden ES . High-performance genetically targetable optical neural silencing by light-driven proton pumps . Nature . 463 . 7277 . 98–102 . January 2010 . 20054397 . 2939492 . 10.1038/nature08652 . 2010Natur.463...98C .
  29. El-Gaby M, Zhang Y, Wolf K, Schwiening CJ, Paulsen O, Shipton OA . 2016 . Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH . Cell Reports . 16 . 8 . 2259–68 . 10.1016/j.celrep.2016.07.057 . 4999416 . 27524609.
  30. Rost BR, Schneider F, Grauel MK, Wozny C, Bentz C, Blessing A, Rosenmund T, Jentsch TJ, Schmitz D, Hegemann P, Rosenmund C . Optogenetic acidification of synaptic vesicles and lysosomes . Nature Neuroscience . 18 . 12 . 1845–1852 . December 2015 . 26551543 . 4869830 . 10.1038/nn.4161 .

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