Archaea SRP is composed of an SRP RNA molecule and two bound proteins named SRP19 and SRP54. Regulated by the binding and hydrolysis of guanosine triphosphates, the RNA-bound SRP54 protein transiently associates not only with the hydrophobic signal sequence as it emerges from the ribosomal exit tunnel, but also interacts with the membrane-associated SRP receptor (FtsY). Comparative analyses of the archaea genomes and their SRP component sequences, combined with structural and biochemical data, support a prominent role of the SRP RNA in the assembly and function of the archaea SRP. The 5e motif, which in eukaryotes binds a 72 kilodalton protein, is preserved in most archaea SRP RNAs despite the lack of an archaea SRP72 homolog. The primary function of the 5e region may be to serve as a hinge, strategically positioned between the small and large SRP domain, allowing the elongated SRP to bind simultaneously to distant ribosomal sites. SRP19, required in eukaryotes for initiating SRP assembly, appears to play a subordinate role in the archaea SRP or may be defunct. The N-terminal A region and a novel C-terminal R region of the archaea SRP receptor (FtsY) are strikingly diverse or absent even among the members of a taxonomic subgroup. 1. Introduction Protein sorting fundamentally maintains the identity and function of every cell with participation of the signal recognition particle (SRP). SRP components have been found in nearly all organisms [1]. Except in chloroplasts, SRP is a ribonucleoprotein [2]. The SRP RNA is typically composed of about 300 nucleotide residues and forms a complex with an extraordinarily conserved protein named SRP54 in archaea and eukarya or Ffh (fifty-four homolog) in the bacteria. A 19？kDa protein, SRP19, is present in archaea and eukarya, but absent in the bacteria. Polypeptides which are homologous to the eukaryal SRP9/14 and SRP68/72 heterodimers have not been found in the archaea genome sequences giving rise to an archaea SRP which is dominated by RNA [3, 4]. SRP interacts with secretory signal or membrane-anchor sequences upon their emergence from the ribosomal exit tunnel. In vitro and in vivo experiments carried out in eukaryotic protein sorting systems have shown that the SRP delays or blocks the translation of the to-be-targeted polypeptides. Translation resumes when the SRP-bound ribosome nascent chain complex (RNC) binds to the membrane-associated FtsY (filamentous temperature sensitive Y) or, in eukaryotes, the alpha subunit of the SRP receptor (SR ). The interaction between SRP54 and the SR increases the affinity of
References
[1]
M. A. Rosenblad, N. Larsen, T. Samuelsson, and C. Zwieb, “Kinship in the SRP RNA family,” RNA Biology, vol. 6, no. 5, pp. 508–516, 2009.
[2]
K. F. Stengel, I. Holdermann, P. Cain, C. Robinson, K. Wild, and I. Sinning, “Structural basis for specific substrate recognition by the chloroplast signal recognition particle protein cpSRP43,” Science, vol. 321, no. 5886, pp. 253–256, 2008.
[3]
C. Zwieb and J. Eichler, “Getting on target: the archaeal signal recognition particle,” Archaea, vol. 1, no. 1, pp. 27–34, 2002.
[4]
R. G. Moll, “The archaeal signal recognition particle: steps toward membrane binding,” Journal of Bioenergetics and Biomembranes, vol. 36, no. 1, pp. 47–53, 2004.
[5]
H. G. Koch, M. Moser, and M. Müller, “Signal recognition particle-dependent protein targeting, universal to all kingdoms of life,” Reviews of Physiology, Biochemistry and Pharmacology, vol. 146, pp. 55–94, 2003.
[6]
K. Nagai, C. Oubridge, A. Kuglstatter, E. Menichelli, C. Isel, and L. Jovine, “Structure, function and evolution of the signal recognition particle,” EMBO Journal, vol. 22, no. 14, pp. 3479–3485, 2003.
[7]
J. A. Doudna and R. T. Batey, “Structural insights into the signal recognition particle,” Annual Review of Biochemistry, vol. 73, pp. 539–557, 2004.
[8]
M. Halic and R. Beckmann, “The signal recognition particle and its interactions during protein targeting,” Current Opinion in Structural Biology, vol. 15, no. 1, pp. 116–125, 2005.
[9]
S.-O. Shan and P. Walter, “Co-translational protein targeting by the signal recognition particle,” FEBS Letters, vol. 579, no. 4, pp. 921–926, 2005.
[10]
G. D. Sprott, “Structures of archaebacterial membrane lipids,” Journal of Bioenergetics and Biomembranes, vol. 24, no. 6, pp. 555–566, 1992.
[11]
J. L. C. M. Van de Vossenberg, A. J. M. Driessen, and W. N. Konings, “The essence of being extremophilic: the role of the unique archaeal membrane lipids,” Extremophiles, vol. 2, no. 3, pp. 163–170, 1998.
[12]
G. von Heijne, “The signal peptide,” Journal of Membrane Biology, vol. 115, no. 3, pp. 195–201, 1990.
[13]
M. Pohlschr？der, M. I. Giménez, and K. F. Jarrell, “Protein transport in Archaea: Sec and twin arginine translocation pathways,” Current Opinion in Microbiology, vol. 8, no. 6, pp. 713–719, 2005.
[14]
S. Y. M. Ng, B. Chaban, D. J. VanDyke, and K. F. Jarrell, “Archaeal signal peptidases,” Microbiology, vol. 153, no. 2, pp. 305–314, 2007.
[15]
S.-V. Albers, Z. Szabó, and A. J. M. Driessen, “Protein secretion in the Archaea: multiple paths towards a unique cell surface,” Nature Reviews Microbiology, vol. 4, no. 7, pp. 537–547, 2006.
[16]
D. Calo and J. Eichler, “Crossing the membrane in Archaea, the third domain of life,” Biochimica et Biophysica Acta. In press.
[17]
J. Yuan, J. C. Zweers, J. M. van Dijl, and R. E. Dalbey, “Protein transport across and into cell membranes in bacteria and archaea,” Cellular and Molecular Life Sciences, vol. 67, no. 2, pp. 179–199, 2010.
[18]
A. Kouranov, L. Xie, J. de la Cruz et al., “The RCSB PDB information portal for structural genomics,” Nucleic Acids Research, vol. 34, pp. D302–305, 2006.
[19]
G. Montoya, K. te Kaat, R. Moll, G. Sch？fer, and I. Sinning, “The crystal structure of the conserved GTPase of SRP54 from the archaeon Acidianus ambivalens and its comparison with related structures suggests a model for the SRP-SRP receptor complex,” Structure, vol. 8, no. 5, pp. 515–525, 2000.
[20]
K. R. Rosendal, K. Wild, G. Montoya, and I. Sinning, “Crystal structure of the complete core of archaeal signal recognition particle and implications for interdomain communication,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 14701–14706, 2003.
[21]
C. Y. Janda, J. Li, C. Oubridge, H. Hernández, C. V. Robinson, and K. Nagai, “Recognition of a signal peptide by the signal recognition particle,” Nature, vol. 465, no. 7297, pp. 507–510, 2010.
[22]
K. Wild, G. Bange, G. Bozkurt, B. Segnitz, A. Hendricks, and I. Sinning, “Structural insights into the assembly of the human and archaeal signal recognition particles,” Acta Crystallographica Section D, vol. 66, no. 3, pp. 295–303, 2010.
[23]
O. N. Pakhomova, S. Deep, Q. Huang, C. Zwieb, and A. P. Hinck, “Solution structure of protein SRP19 of Archaeoglobus fulgidus signal recognition particle,” Journal of Molecular Biology, vol. 317, no. 1, pp. 145–158, 2002.
[24]
U. Ilangovan, S. H. Bhuiyan, C. S. Hinck et al., “A. fulgidus SRP54 M-domain,” Journal of Biomolecular NMR, vol. 41, no. 4, pp. 241–248, 2008.
[25]
T. Hainz, S. Huang, and A. E. Sauer-Eriksson, “Interaction of signal-recognition particle 54 GTPase domain and signal-recognition particle RNA in the free signal-recognition particle,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 38, pp. 14911–14916, 2007.
[26]
T. Hainzl, S. Huang, and A. E. Sauer-Eriksson, “Structure of the SRP19-RNA complex and implications for signal recognition particle assembly,” Nature, vol. 417, no. 6890, pp. 767–771, 2002.
[27]
T. Hainzl, S. Huang, and A. E. Sauer-Eriksson, “Structural insights into SRP RNA: an induced fit mechanism for SRP assembly,” RNA, vol. 11, no. 7, pp. 1043–1050, 2005.
[28]
W. M. Clemons Jr., K. Gowda, S. D. Black, C. Zwieb, and V. Ramakrishnan, “Crystal structure of the conserved subdomain of human protein SRP54M at 2.1 ？ resolution: evidence for the mechanism of signal peptide binding,” Journal of Molecular Biology, vol. 292, no. 3, pp. 697–705, 1999.
[29]
P. F. Egea, J. Napetschnig, P. Walter, and R. M. Stroud, “Structures of SRP54 and SRP19, the two proteins that organize the ribonucleic core of the signal recognition particle from Pyrococcus furiosus,” PLoS One, vol. 3, no. 10, Article ID e3528, 2008.
[30]
P. F. Egea, H. Tsuruta, G. P. de Leon, J. Napetschnig, P. Walter, and R. M. Stroud, “Structures of the signal recognition particle receptor from the Archaeon Pyrococcus furiosus: Implications for the targeting step at the membrane,” PLoS One, vol. 3, no. 11, Article ID e3619, 2008.
[31]
J. M. Kollman and R. F. Doolittle, “Determining the relative rates of change for prokaryotic and eukaryotic proteins with anciently duplicated paralogs,” Journal of Molecular Evolution, vol. 51, no. 2, pp. 173–181, 2000.
[32]
N. Larsen and C. Zwieb, “SRP-RNA sequence alignment and secondary structure,” Nucleic Acids Research, vol. 19, no. 2, pp. 209–215, 1991.
[33]
C. Zwieb, R. W. Van Nues, M. A. Rosenblad, J. D. Brown, and T. Samuelsson, “A nomenclature for all signal recognition particle RNAs,” RNA, vol. 11, no. 1, pp. 7–13, 2005.
[34]
M. Halic, T. Becker, M. R. Pool et al., “Structure of the signal recognition particle interacting with the elongation-arrested ribosome,” Nature, vol. 427, no. 6977, pp. 808–814, 2004.
[35]
D. A. Benson, I. Karsch-Mizrachi, D. J. Lipman, J. Ostell, and E. W. Sayers, “GenBank,” Nucleic Acids Research, vol. 37, database issue, pp. D26–D31, 2009.
[36]
O. Weichenrieder, K. Wild, K. Strub, and S. Cusack, “Structure and assembly of the Alu domain of the mammalian signal recognition particle,” Nature, vol. 408, no. 6809, pp. 167–173, 2000.
[37]
E. S. Andersen, M. A. Rosenblad, N. Larsen et al., “The tmRDB and SRPDB resources,” Nucleic acids research., vol. 34, pp. D163–168, 2006.
[38]
M. Regalia, M. A. Rosenblad, and T. Samuelsson, “Prediction of signal recognition particle RNA genes,” Nucleic Acids Research, vol. 30, no. 15, pp. 3368–3377, 2002.
[39]
E. Iakhiaeva, J. Wower, I. K. Wower, and C. Zwieb, “The 5e motif of eukaryotic signal recognition particle RNA contains a conserved adenosine for the binding of SRP72,” RNA, vol. 14, no. 6, pp. 1143–1153, 2008.
[40]
E. Iakhiaeva, J. Yin, and C. Zwieb, “Identification of an RNA-binding domain in human SRP72,” Journal of Molecular Biology, vol. 345, no. 4, pp. 659–666, 2005.
[41]
C. Darwin, “Modes of transition,” in The Origin of Species, chapter 6, John Murray, London, UK, 1859.
[42]
S. J. Gould and E. S. Vrba, “Exaptation—a missing term in the science of form,” Paleobiology, vol. 8, no. 1, pp. 4–15, 1982.
[43]
S. Nolivos, A. J. Carpousis, and B. Clouet-d'Orval, “The K-loop, a general feature of the Pyrococcus C/D guide RNAs, is an RNA structural motif related to the K-turn,” Nucleic Acids Research, vol. 33, no. 20, pp. 6507–6514, 2005.
[44]
R. Stefl, L. Skrisovska, and F. H.-T. Allain, “RNA sequence- and shape-dependent recognition by proteins in the ribonucleoprotein particle,” EMBO Reports, vol. 6, no. 1, pp. 33–38, 2005.
[45]
J. C. Politz, S. Yarovoi, S. M. Kilroy, K. Gowda, C. Zwieb, and T. Pederson, “Signal recognition particle components in the nucleolus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 1, pp. 55–60, 2000.
[46]
T. S. Maity and K. M. Weeks, “A threefold RNA-protein interface in the signal recognition particle gates native complex assembly,” Journal of Molecular Biology, vol. 369, no. 2, pp. 512–524, 2007.
[47]
H. Maeshima, E. Okuno, T. Aimi, T. Morinaga, and T. Itoh, “An archaeal protein homologous to mammalian SRP54 and bacterial Ffh recognizes a highly conserved region of SRP RNA,” FEBS Letters, vol. 507, no. 3, pp. 336–340, 2001.
[48]
I. Tozik, Q. Huang, C. Zwieb, and J. Eichler, “Reconstitution of the signal recognition particle of the halophilic archaeon Haloferax volcanii,” Nucleic Acids Research, vol. 30, no. 19, pp. 4166–4175, 2002.
[49]
J. Yin, Q. Huang, O. N. Pakhomova, A. P. Hinck, and C. Zwieb, “The conserved adenosine in helix 6 of Archaeoglobus fulgidus signal recognition particle RNA initiates SRP assembly,” Archaea, vol. 1, no. 4, pp. 269–275, 2004.
[50]
A. Kuglstatter, C. Oubridge, and K. Nagai, “Induced structural changes of 7SL RNA during the assembly of human signal recognition particle,” Nature Structural Biology, vol. 9, no. 10, pp. 740–744, 2002.
[51]
M. Sánchez, J.-M. Beckerich, C. Gaillardin, and A. Domínguez, “Isolation and cloning of the Yarrowia lipolytica SEC65 gene, a component of the yeast signal recognition particle displaying homology with the human SRP19 gene,” Gene, vol. 203, no. 1, pp. 75–84, 1997.
[52]
S. Yurist, I. Dahan, and J. Eichler, “SRP19 is a dispensable component of the signal recognition particle in Archaea,” Journal of Bacteriology, vol. 189, no. 1, pp. 276–279, 2007.
[53]
R. W. Rose and M. Pohlschr？der, “In vivo analysis of an essential archaeal signal recognition particle in its native host,” Journal of Bacteriology, vol. 184, no. 12, pp. 3260–3267, 2002.
[54]
C. Moser, O. Mol, R. S. Goody, and I. Sinning, “The signal recognition particle receptor of Escherichia coli (FtsY) has a nucleotide exchange factor built into the GTPase domain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 21, pp. 11339–11344, 1997.
[55]
P. J. Rapiejko and R. Gilmore, “Empty site forms of the SRP54 and SRα GTPase mediate targeting of ribosome-nascent chain complexes to the endoplasmic reticulum,” Cell, vol. 89, no. 5, pp. 703–713, 1997.
[56]
R. J. Keenan, D. M. Freymann, P. Walter, and R. M. Stroud, “Crystal structure of the signal sequence binding subunit of the signal recognition particle,” Cell, vol. 94, no. 2, pp. 181–191, 1998.
[57]
R. T. Batey, R. P. Rambo, L. Lucast, B. Rha, and J. A. Doudna, “Crystal structure of the ribonucleoprotein core of the signal recognition particle,” Science, vol. 287, no. 5456, pp. 1232–1239, 2000.
[58]
J. A. Newitt and H. D. Bernstein, “The N-domain of the signal recognition particle 54-kDa subunit promotes efficient signal sequence binding,” European Journal of Biochemistry, vol. 245, no. 3, pp. 720–729, 1997.
[59]
E. M. Clérico, A. Szymanska, and L. M. Gierasch, “Exploring the interactions between signal sequences and E. coli SRP by two distinct and complementary crosslinking methods,” Biopolymers, vol. 92, no. 3, pp. 201–211, 2009.
[60]
J. D. Miller, H. D. Bernstein, and P. Walter, “Interaction of E. coli Ffh/4.5S ribonucleoprotein and FtsY mimics that of mammalian signal recognition particle and its receptor,” Nature, vol. 367, no. 6464, pp. 657–659, 1994.
[61]
S. Althoff, D. Selinger, and J. A. Wise, “Molecular evolution of SRP cycle components: functional implications,” Nucleic Acids Research, vol. 22, no. 11, pp. 1933–1947, 1994.
[62]
S. Gribaldo and P. Cammarano, “The root of the universal tree of life inferred from anciently duplicated genes encoding components of the protein-targeting machinery,” Journal of Molecular Evolution, vol. 47, no. 5, pp. 508–516, 1998.
[63]
P. F. Egea, S.-O. Shan, J. Napetschnig, D. F. Savage, P. Walter, and R. M. Stroud, “Substrate twinning activates the signal recognition particle and its receptor,” Nature, vol. 427, no. 6971, pp. 215–221, 2004.
[64]
A. Zelazny, A. Seluanov, A. Cooper, and E. Bibi, “The NG domain of the prokaryotic signal recognition particle receptor, FtsY, is fully functional when fused to an unrelated integral membrane polypeptide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 12, pp. 6025–6029, 1997.
[65]
E. Bibi, A. A. Herskovits, E. S. Bochkareva, and A. Zelazny, “Putative integral membrane SRP receptors,” Trends in Biochemical Sciences, vol. 26, no. 1, pp. 15–16, 2001.
[66]
S. A. Ladefoged and G. Christiansen, “A GTP-binding protein of Mycoplasma hominis: a small sized homolog to the signal recognition particle receptor FtsY,” Gene, vol. 201, no. 1-2, pp. 37–44, 1997.
[67]
I. V. Shepotinovskaya and D. M. Freymann, “Conformational change of the N-domain on formation of the complex between the GTPase domains of Thermus aquaticus Ffh and FtsY,” Biochimica et Biophysica Acta, vol. 1597, no. 1, pp. 107–114, 2002.
[68]
T. Lichi, G. Ring, and J. Eichler, “Membrane binding of SRP pathway components in the halophilic archaea Haloferax volcanii,” European Journal of Biochemistry, vol. 271, no. 7, pp. 1382–1390, 2004.
[69]
A. Haddad, R. W. Rose, and M. Pohlschr？der, “The Haloferax volcanii FtsY homolog is critical for haloarchaeal growth but does not require the A domain,” Journal of Bacteriology, vol. 187, no. 12, pp. 4015–4022, 2005.
[70]
J. Luirink, C. M. Ten Hagen-Jongman, C. C. van der Weijden et al., “An alternative protein targeting pathway in Escherichia coli: Studies on the role of FtsY,” EMBO Journal, vol. 13, no. 10, pp. 2289–2296, 1994.
[71]
H.-J. Dong, J.-Y. Jiang, and Y.-Q. Li, “The distinct anchoring mechanism of FtsY from different microbes,” Current Microbiology, vol. 59, no. 3, pp. 336–340, 2009.
[72]
M. Mircheva, D. Boy, B. Weiche, F. Hucke, P. Graumann, and H.-G. Koch, “Predominant membrane localization is an essential feature of the bacterial signal recognition particle receptor,” BMC Biology, vol. 7, article no. 76, 2009.
[73]
E. de Leeuw, D. Poland, O. Mol et al., “Membrane association of FtsY, the E. coli SRP receptor,” FEBS Letters, vol. 416, no. 3, pp. 225–229, 1997.
[74]
E. de Leeuw, K. te Kaat, C. Moser et al., “Anionic phospholipids are involved in membrane association of FtsY and stimulate its GTPase activity,” EMBO Journal, vol. 19, no. 4, pp. 531–541, 2000.
[75]
R. Parlitz, A. Eitan, G. Stjepanovic et al., “Escherichia coli signal recognition particle receptor FtsY contains an essential and autonomous membrane-binding amphipathic helix,” Journal of Biological Chemistry, vol. 282, no. 44, pp. 32176–32184, 2007.
[76]
N. J. Marty, D. Rajalingam, A. D. Kight et al., “The membrane-binding motif of the chloroplast signal recognition particle receptor (cpFtsY) regulates GTPase activity,” Journal of Biological Chemistry, vol. 284, no. 22, pp. 14891–14903, 2009.
[77]
S. Angelini, S. Deitermann, and H.-G. Koch, “FtsY, the bacterial signal-recognition particle receptor, interacts functionally and physically with the SecYEG translocon,” EMBO Reports, vol. 6, no. 5, pp. 476–481, 2005.
[78]
B. Weiche, J. Bürk, S. Angelini, E. Schiltz, J. O. Thumfart, and H.-G. Koch, “A cleavable N-terminal membrane anchor is involved in membrane binding of the Escherichia coli SRP receptor,” Journal of Molecular Biology, vol. 377, no. 3, pp. 761–773, 2008.
[79]
L. Bahari, R. Parlitz, A. Eitan et al., “Membrane targeting of ribosomes and their release require distinct and separable functions of FtsY,” Journal of Biological Chemistry, vol. 282, no. 44, pp. 32168–32175, 2007.
[80]
R. Moll, S. Schmidtke, and G. Sch？fer, “Domain structure, GTP-hydrolyzing activity and 7S RNA binding of Acidianus ambivalens Ffh-homologous protein suggest an SRP-like complex in archaea,” European Journal of Biochemistry, vol. 259, no. 1-2, pp. 441–448, 1999.
[81]
S. H. Bhuiyan, K. Gowda, H. Hotokezaka, and C. Zwieb, “Assembly of archaeal signal recognition particle from recombinant components,” Nucleic Acids Research, vol. 28, no. 6, pp. 1365–1373, 2000.
[82]
J. L. Diener and C. Wilson, “Role of SRP19 in assembly of the Archaeoglobus fulgidus signal recognition particle,” Biochemistry, vol. 39, no. 42, pp. 12862–12874, 2000.
[83]
R. Gropp, F. Gropp, and M. C. Betlach, “Association of the halobacterial 7S RNA to the polysome correlates with expression of the membrane protein bacterioopsin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 4, pp. 1204–1208, 1992.
[84]
H. Dale and M. P. Krebs, “Membrane insertion kinetics of a protein domain in vivo. The bacterioopsin N terminus inserts co-translationally,” Journal of Biological Chemistry, vol. 274, no. 32, pp. 22693–22698, 1999.
[85]
H. Dale, C. M. Angevine, and M. P. Krebs, “Ordered membrane insertion of an archaeal opsin in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 14, pp. 7847–7852, 2000.
[86]
G. Ring and J. Eichler, “Extreme secretion: protein translocation across the archaleal plasma membrane,” Journal of Bioenergetics and Biomembranes, vol. 36, no. 1, pp. 35–45, 2004.
[87]
R. Ortenberg and M. Mevarech, “Evidence for post-translational membrane insertion of the integral membrane protein bacterioopsin expressed in the heterologous halophilic archaeon Haloferax volcanii,” Journal of Biological Chemistry, vol. 275, no. 30, pp. 22839–22846, 2000.
[88]
K. Wild, M. Halic, I. Sinning, and R. Beckmann, “SRP meets the ribosome,” Nature Structural and Molecular Biology, vol. 11, no. 11, pp. 1049–1053, 2004.
[89]
A. K. K. Lakkaraju, C. Mary, A. Scherrer, A. E. Johnson, and K. Strub, “SRP keeps polypeptides translocation-competent by slowing translation to match limiting ER-targeting sites,” Cell, vol. 133, no. 3, pp. 440–451, 2008.
[90]
S. McGinnis and T. L. Madden, “BLAST: at the core of a powerful and diverse set of sequence analysis tools,” Nucleic Acids Research, vol. 32, pp. W20–W25, 2004.
[91]
E. S. Andersen, A. Lind-Thomsen, B. Knudsen et al., “Semiautomated improvement of RNA alignments,” RNA, vol. 13, no. 11, pp. 1850–1859, 2007.
[92]
R. C. Edgar, “MUSCLE: multiple sequence alignment with high accuracy and high throughput,” Nucleic Acids Research, vol. 32, no. 5, pp. 1792–1797, 2004.
[93]
M. Clamp, J. Cuff, S. M. Searle, and G. J. Barton, “The Jalview Java alignment editor,” Bioinformatics, vol. 20, no. 3, pp. 426–427, 2004.
