Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK1
Tel: +44 24 76528360. Fax: +44 24 76523701. e-mail: abolhuis{at}bio.warwick.ac.uk
Keywords: archaea, Sec pathway, Tat pathway, signal peptide, lipoprotein
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Background |
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Systems for the transport of proteins across membranes function by common principles in all domains of life (Schatz & Dobberstein, 1996 ). Proteins destined for export are usually synthesized as pre-proteins with an amino-terminal signal peptide that is required for targeting to the membrane and initiation of protein translocation (von Heijne, 1990
). At the membrane, pre-proteins are transported through a proteinaceous translocation channel in a process that is driven by the binding and hydrolysis of nucleoside triphosphates and/or the proton motive force. During or shortly after translocation, the signal peptide is removed from the pre-protein by signal peptidases (SPases), and the mature protein is released at the trans side of the membrane. Systems of protein transport that function according to these basic principles include protein import into mitochondria, chloroplasts and the lumen of the endoplasmic reticulum (ER), and protein export to extracytoplasmic compartments of prokaryotes, such as the periplasm and outer membrane (Gram-negative bacteria), the cell wall (Gram-positive bacteria and archaea) and the growth medium.
Halobacterium species are excellent model organisms among the archaea. These organisms are true extremophiles that thrive in an environment that is nearly saturated with salt (45 M NaCl). In contrast to several other archaea, halobacteria are easy to culture as they usually grow aerobically between 30 and 40 °C. Furthermore, they are genetically amenable organisms for which several genetic tools are available, such as transformation, shuttle vectors and gene knockout strategies (Sowers & Schreier, 1999 ; Peck et al., 2000
). As with other archaea, little is known about the transport of proteins in these organisms. Nevertheless, the availability of the genomic sequences, including that of Halobacterium sp. NRC-1 (Ng et al., 2000
), provides a wealth of information that can be used to make predictions about various cellular processes. This review will focus primarily on the two major protein transport routes found in archaea, i.e. the Sec and the Tat pathways, and the identification of proteins in Halobacterium sp. NRC-1 that may use these pathways to reach their extracytoplasmic destination. The analyses described in this review show that, in contrast to most other organisms, the majority of secretory proteins of Halobacterium sp. NRC-1 use the Tat pathway for export. In addition, there is the unexpected finding of many putative lipoproteins in this archaeon, which, as discussed below, indicates the presence of a completely novel mechanism for lipo-modification and processing in archaea.
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The Sec pathway |
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In bacteria, most extracytoplasmic proteins are targeted post-translationally, with the aid of a targeting factor such as SecB, to the translocase, which comprises SecY, SecE and SecG (for a review, see Manting & Driessen, 2000 ). SecY and SecE are related to the eukaryotic Sec61
and Sec61
, respectively. SecG and Sec61ß are not related, but may have the same role in protein translocation. A pivotal role in bacterial protein transport is played by the peripheral membrane protein SecA, which is an ATPase that pushes the pre-protein through the translocase channel (Economou, 1998
). Protein translocation is assisted by accessory components such as SecD and SecF. During, or shortly after, translocation, the signal peptide is removed by a type I SPase (Dalbey et al., 1997
) or, in case of lipoproteins (see below), by a type II SPase (Hayashi & Wu, 1990
).
Several membrane proteins that use the Sec machinery for integration into the membrane are targeted by an SRP-like complex that comprises a homologue of SRP54 (Ffh) and a 4·5S RNA molecule (Seluanov & Bibi, 1997 ; Ulbrandt et al., 1997
). Targeting is mediated by a homologue of the eukaryotic SR
called FtsY. For certain proteins SecA is still required for SRP-dependent translocation (Neumann-Haefelin et al., 2000
), indicating that their translocation is not driven by the ribosome. The integral membrane protein YidC is also vital for the insertion of membrane proteins in Escherichia coli (Dalbey & Kuhn, 2000
). This protein, which interacts with the SecYEG complex (Beck et al., 2001
; Scotti et al., 2000
), is also involved in the insertion of Sec-independent membrane proteins (Samuelson et al., 2000
).
Archaea lack the chaperone SecB, but do contain an SRP pathway (Eichler & Moll, 2001 ). The archaeal components of this pathway are SRP54, SRP19 (which is absent in bacteria), 7S RNA, and a homologue of SR
/FtsY (denoted Dpa in Halobacterium sp. NRC-1). Analysis of the SRP pathway in the halophilic archaeon Haloferax volcanii showed that SRP54 is essential for viability and that it interacts with SRP19 and 7S RNA (Rose & Pohlschröder, 2002
). All archaea contain homologues of SecY/Sec61
and SecE/Sec61
but, interestingly, these are more similar to their eukaryotic counterparts (Pohlschröder et al., 1997
; Eichler, 2000
). A SecG homologue is not present in archaea, but a recent study suggested the presence of a homologue of the eukaryotic protein Sec61ß (Kinch et al., 2002
). Strikingly, archaea lack the bacterial translocation motor SecA. Thus archaea may use an alternative unique form of motor protein, or use an entirely different translocation mechanism that is possibly similar to the eukaryotic co-translational translocation mechanism. Since the archaeal translocase and SRP show more similarity to those found in eukaryotes, the latter possibility seems to be the most likely one. It is interesting to note, however, that of the accessory components only homologues of the bacterial SecD and SecF proteins are present. The role of these proteins is not clear, but they have been proposed to be involved in the membrane cycling of SecA (Duong & Wickner, 1997
). Thus it is conceivable that SecD and SecF are involved in the cycling of a protein with a function similar to SecA. It is also possible that SecD and SecF serve a completely different role in archaea, or that the effect of SecD and SecF on SecA cycling is only indirect and that they have a different function in bacterial protein translocation as well. Strikingly, other roles have also been proposed for SecD/F in bacteria, such as involvement in the release of the mature secretory protein from the translocase (Matsuyama et al., 1993
), gating or assembly of the translocase channel (Pohlschröder et al., 1997
), or removal of signal peptides from the translocase (Bolhuis et al., 1998
). The latter function is compatible with the observation that SecD and SecF show similarity to secondary solute transporters (Bolhuis et al., 1998
; Tseng et al., 1999
). Notably, the previously suggested function of SecD and SecF in maintenance of the proton motive force (Arkowitz & Wickner, 1994
) was recently refuted (Nouwen et al., 2001
). Archaea lack a number of components that are pivotal for protein transport in bacteria or eukarya, including homologues of the bacterial YidC protein and the eukaryotic TRAM and Sec63 proteins. Therefore, it is very likely that novel components will be involved in the archaeal translocation process.
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The Tat pathway |
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Bacteria and thylakoid membranes of chloroplasts usually contain three major membrane-bound components that are required for Tat-dependent export (for reviews, see Berks et al., 2000 ; Robinson & Bolhuis, 2001
). The core of the E. coli Tat-translocase is probably formed by TatB and TatC, both of which are present in a strict 1:1 ratio (Bolhuis et al., 2001
). These proteins function together with a third component, TatA. Similarly, chloroplast Hcf106 (a TatB homologue) and TatC are tightly associated with each other and interact only with Tha4 (a TatA homologue) in the presence of precursor protein (Mori & Cline, 2002
). TatA and TatB are similar in structure and contain one transmembrane helix at the N-terminus followed by a cytoplasmic domain. TatC is an integral membrane protein with six transmembrane helices (Fig. 1a
).
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Simple BLAST searches did not immediately show the presence of TatA- or TatB-like proteins in Halobacterium sp. NRC-1, but with PSI-BLAST (Altschul et al., 1997 ) a protein was identified showing similarity to TatA of E. coli (45% identical and conservative replacements; Fig. 2
). This protein, denoted Vng0801, is predicted to contain an N-terminal membrane-spanning domain that ends on the FG motif that is diagnostic for proteins belonging to the TatA family (Robinson & Bolhuis, 2001
). Like other TatA- and TatB-like proteins (Settles et al., 1997
), the membrane-spanning domain of Vng0801 is followed by a stretch of approximately 30 residues that may form an amphipathic helix. A protein belonging to the TatB family was not identified in Halobacterium sp. NRC-1.
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Signal peptides |
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Class II signal peptides are found in bacterial lipoproteins. These signal peptides, which contain similar N- and H-domains to Class I signal peptides, are characterized by a conserved lipobox in the C-domain with the consensus sequence L(A/S)(G/A)C (von Heijne, 1989 ; Hayashi & Wu, 1990
). The invariable cysteine in this lipobox is lipid-modified by a diacylglyceryl transferase and becomes the first residue of the mature protein after cleavage by a lipoprotein-specific type II SPase. Due to the lipid-modified cysteine, the protein remains anchored to the cytoplasmic membrane. Most Class II signal peptides are predicted to be Sec-dependent, since twin-arginine motifs are only rarely found in these signal peptides (Tjalsma et al., 2000
).
The third class of signal peptides are present in prepilin-like proteins. These signal peptides also have a positively charged N-domain and a hydrophobic H-domain. In contrast to other signal peptides, prepilin signal peptides are cleaved just before the H-domain by a specific SPase that has its active site on the cytoplasmic face of the membrane (Lory, 1994 ). The H-domain, which remains attached to the mature protein, plays an important role in the assembly of the prepilin-like structures (Forest & Tainer, 1997
).
The fourth class of signal peptides are found in certain bacteriocins and pheromones that are exported by ABC transporters. These lack a hydrophobic domain, and only some of them contain a double glycine motif at the -1 and -2 positions relative to the cleavage site (Michiels et al., 2001 ).
Only few extracellular or wall-bound proteins from archaea have been described. Through genomic analysis, the eurarchaeon Methanococcus jannaschii was predicted to contain at least 34 secretory proteins (Nielsen et al., 1999 ), but the criteria used for identification of proteins containing signal peptides were rather conservative and it is likely that several were not identified. Recently, a more extensive survey was performed on the genome of Sulfolobus solfataricus, a member of the crenarchaeotes (Albers & Driessen, 2002
). In that case, 131 putative secretory proteins were identified. The main conclusions from these studies were that archaeal class I signal peptides have a bacterial-like charge distribution and a eukaryotic-like cleavage site. Very recently, Rose et al. (2002)
developed a software program called TATFIND that is able to identify Tat-dependent substrates in any sequenced genome. They identified several Tat-dependent substrates in Halobacterium sp. NRC-1 and other archaea, and concluded that haloarchaea use the Tat pathway extensively.
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Signal peptide predictions in Halobacterium sp. NRC-1 |
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Sec-type signal peptides
The analysis resulted in the identification of 28 proteins that are putative substrates for the Sec pathway and cleaved by type I SPase (Table 1). This represents 1% of the proteome, which is relatively low as compared with for instance Bacillus subtilis (4%; Tjalsma et al., 2000
), E. coli (6%; unpublished results) or S. solfataricus (4%; Albers & Driessen, 2002
). The N-regions of these signal peptides usually contain one or two positively charged residues, with a strong bias to arginines (18% Lys, 82% Arg). This bias, however, does not seem to be limited to N-regions of signal peptides, as a similar ratio is found in the entire proteome of Halobacterium sp. NRC-1 (21% Lys, 79% Arg). In contrast to predicted signal peptides of M. jannaschii and S. solfataricus (Nielsen et al., 1999
; Albers & Driessen, 2002
), there is not an increased isoleucine content in the H-domain. Because archaeal SPases are more closely related to their eukaryotic counterparts (Tjalsma et al., 1998
), the cleavage sites indicated in Table 1
were based upon the predictions of the eukaryotic dataset in SignalP. The cleavage site of the cell-surface glycoprotein Csg, which is one of the very few that has been determined experimentally (Lechner & Sumper, 1987
), was correctly predicted.
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Tat-type signal peptides
The signal peptide searches revealed 18 putative substrates for the Tat pathway (Table 2). This is 40% of the Class I signal peptides, which is surprisingly high as compared to for instance B. subtilis (8%; Tjalsma et al., 2000
), E. coli (9%; unpublished data) or S. solfataricus (2·5%; Albers & Driessen, 2002
). Several of the putative Tat-type signal peptides also contain the remainder of the bacterial RR motif, including the signal peptide of DmsA (DMSO reductase). The latter protein, which is predicted to bind a molybdopterin cofactor, is a typical Tat substrate that is involved in anaerobic respiration. Notably, Halobacterium species have, to my knowledge, never been reported to grow anaerobically using DMSO as the terminal electron acceptor. Several proteins that contain Tat-signal peptides are normally Sec-dependent in bacteria and do not bind cofactors, such as the subtilisin-like protease Sub and the alkaline phosphatase Aph. Interestingly, alkaline phosphatase from the thermophilic bacterium Thermus thermophilus was recently shown to be a Tat-dependent substrate (Angelini et al., 2001
). In this study, it was speculated that the Tat pathway could be a more suitable transport route for thermophilic enzymes because they are more rigidly folded.
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Type IV prepilin signal peptides
In archaea, flagellin proteins contain a signal peptide that is similar to that of type IV prepilins (see Thomas et al., 2001 ). It is not known how these signal peptides are cleaved, as archaea lack a prepilin-type SPase, or how these flagellin proteins are translocated across the cytoplasmic membrane (Thomas et al., 2001
). Interestingly, the archaeon S. solfataricus contains several sugar-binding proteins with a similar signal peptide, and for some of these the cleavage site, which is located just before the hydrophobic domain, was experimentally verified (Albers & Driessen, 2002
). Strikingly, most binding proteins of Halobacterium sp. NRC-1 seem to be retained at the membrane through lipo-modification and not through the hydrophobic domain of a prepilin-like signal peptide (Table 4
). The genome of Halobacterium sp. NRC-1 does encode six flagellin proteins, all of which have very similar prepilin-like signal peptides (Table 5
; Ng et al., 2000
). Four genes that are closely located on the chromosome (vng0198, vng0199, vng0200 and vng0204; see Tables 1
and 2
) encode proteins containing the same residues as the flagellin proteins in their cleavage site (RGQ). The processing of these proteins should, however, be experimentally determined as they also contain a predicted cleavage site for type I SPase.
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Concluding remarks |
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In conclusion, several novel aspects can be found in the protein transport pathways of Halobacterium sp. NRC-1, some of which may be specific for halophiles. Depending on the environment in which they thrive, specific adaptations may indeed be found in other archaea as well. Nevertheless, because of the genetic amenability and ease of culturing, Halobacterium species are very good model systems to study protein translocation in archaea and provide a fundamental insight into an important aspect of the cell biology of the third domain of life.
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ACKNOWLEDGEMENTS |
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