Type II secretion system

Last updated
Bacterial type II and III secretion system protein
Identifiers
SymbolSecretin
Pfam PF00263
InterPro IPR004846
TCDB 3.A.5
OPM superfamily 348
OPM protein 5wln
Membranome 430
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The type 2 secretion system (often referred to as the type II secretion system or by the initials T2SS) is a type of protein secretion machinery found in various species of Gram-negative bacteria, including many human pathogens such as Pseudomonas aeruginosa and Vibrio cholerae . [1] The type II secretion system is one of six protein secretory systems commonly found in Gram-negative bacteria, along with the type I, type III, and type IV secretion systems, as well as the chaperone/usher pathway, the autotransporter pathway/type V secretion system, and the type VI secretion system (some bacteria also utilize the type VII secretion system). [2] Like these other systems, the type II secretion system enables the transport of cytoplasmic proteins across the lipid bilayers that make up the cell membranes of Gram-negative bacteria. Secretion of proteins and effector molecules out of the cell plays a critical role in signaling other cells and in the invasion and parasitism of host cells.

Contents

Overview

The type II secretion system is a membrane-bound protein complex found in Gram-negative bacteria that is used to secrete proteins found in the cytoplasm of the bacteria into the extracellular space outside of the cell. The type II secretion system is just one of many secretory systems found in Gram-negative bacteria and is used to secrete a variety of different proteins, including bacterial toxins and degradative enzymes such as proteases and lipases. These secreted proteins are generally associated with the breakdown of host tissues and therefore are often important in causing the symptoms associated with certain bacterial infections. [3] Each bacterial cell may contain a number of type II secretion complexes, which are found embedded in the inner and outer membranes of the cell.

Along with other secretory systems such as the chaperone/usher pathway and the type IV secretion system, type II secretion is a two-step process. The first step involves the Sec and Tat secretory pathways, which are responsible for transporting proteins across the inner membrane into the periplasm. [4] For instance, the Sec pathway is used to transport structural components of the type II secretion system into the periplasm where they can then assemble, while both the Sec and Tat pathways are used to transport secretory proteins into the periplasm. Once these secretory proteins are located in the periplasm, the second step can then take place, whereby they are secreted across the outer membrane into the extracellular milieu.

Structure

T2SS.svg

Overall the type II secretion system is a large multiprotein machinery, made up of a number of distinct protein subunits known as the general secretory proteins (GSPs). [5] The genes encoding these GSPs are usually found together in the genome in a single operon and many of these genes overlap. Each gene is named with a letter corresponding to the GSP that it encodes (for example the gspD gene encodes GspD) and studies indicate that between 12 and 15 of these genes are essential to the function of the type II secretion system. [6] The GSPs are common among a number of different bacterial species and when they come together they form a complex that is structurally very similar to the type IV pili, an appendage that is also commonly found in gram negative bacteria. [7] Overall the type II secretion system can be broken down into four main components. These are the outer membrane complex, the inner membrane complex, the secretion ATPase and the pseudopilus.

Outer Membrane Complex

The outer membrane complex is made up largely by the secretin GspD. [8] Secretins are β-barrels that are found in membrane where they form channels that allow substances to move in or out of cells. [9] In the type II secretion system GspD creates a pore in the outer membrane of the bacterial cell through which proteins can be secreted. As a result, GspD is essential for the correct function system because without it secretory proteins cannot exit the cell. GspD is transported into the periplasm via the Sec translocon and is then inserted into the outer membrane. This insertion is not spontaneous however and is often reliant upon the β-barrel assembly machinery which ensures β-barrel proteins are folded correctly before insertion into the membrane. [10]

GspD is often found associated with the lipoprotein GspS. GspS is also transported into the periplasm using the Sec translocation machinery, at which point it is inserted into the inner layer of the outer membrane where it remains closely associated with GspD. It is thought that GspS plays an important role in the stabilization of the secretin GspD and helps prevent it from breaking down in the presence of highly degradative periplasmic enzymes. [8]

Inner Membrane Complex

The inner membrane complex is made up of several different Gsp proteins which are embedded in the inner membrane. Like the outer membrane secretin GspD these proteins are transported into the periplasm via the Sec translocation pathway before being inserted into the inner membrane. Four different proteins make up the inner membrane complex; these are GspC, GspF, GspL and GspM. [5]

Each of these individual subunits plays a slightly different role. GspC for instance has been shown to interact with GspD. This interaction helps gate the type II secretion system and only when this gate is open are secretory proteins able to enter the system and be pumped out of the cell. Importantly, when associated together, GspC, GspL and GspM help protect each other from proteolytic enzymes that would otherwise degrade them. Unlike the other proteins that make up the inner membrane complex GspF is a multipass transmembrane protein and it may play a role in binding the secretion ATPase. GspL is however known to form tight interactions with the secretion ATPase and these are needed to hold it in close association with the rest of the inner membrane complex. [11]

Secretion ATPase

The secretion ATPase, GspE, is an ATPase which is found closely associated with the inner membrane complex on the cytoplasmic side of the inner membrane. [12] GspE belongs to the type II/type IV secretion ATPase family. ATPases belonging to this family have a distinct hexameric structure. Each individual subunit of the hexamer has 3 main domains. These are 2 separate N-terminal domains called N1D and N2D which are separated by a short linker region and a single C-terminal domain termed the CTD. The CTD in turn is made up of 3 subdomains, one of which is a nucleotide binding domain. It is this nucleotide binding domain, which is present in of each of the 6 subunits of the hexamer, that is responsible for binding ATP. The other 2 domains that make up the CTD, a four helical domain and a metal binding domain, then help catalyze the hydrolysis of bound ATP. [12] This ATP hydrolysis is used to power the assembly and disassembly of the pseudopillus which is what drives secretion via the type II secretion system. As a result, the system cannot function without GspE. The N-terminal domains N1D and N2D form the interactions with the inner membrane complex which help keep the secretion ATPase in close association with the rest of the type II secretion system. The N2D domain is not fully understood but observations show that it is the N1D which is responsible for forming the tight interactions seen with the inner membrane complex subunit GspL.

Pseudopilus

The pseudopilus is found in the periplasm but does not extend out through the secretin GspD into the extracellular milieu. Its name it derived from the fact that it is made up of a number of pilin like proteins or pseudopilins, known as GspG, GspH, GspI, GspJ and GspK. [3] They are known as pseudopilins due to their similarity to the pilins (like PilA) that make up the type IV pili found in gram negative bacteria. Like their counterparts, the pseudopilins are initially produced in an immature form. These pre-pseudopilins consist of an N-terminal signal sequence that targets the proteins to the Sec translocon and a long C-terminal passenger domain which encodes the actual pseudopilin protein itself. Once the Sec machinery has transported the pre-pseudopilin across the inner membrane, but before the protein itself is released into the periplasm, the N-terminal signal sequence is cleaved at a conserved stretch of positively charged amino acid residues. This cleavage is catalysed by the signal peptidase GspO and the end result is the removal of the N-terminal signal sequence and the formation of a mature pseudopilin. [5] GspO is inserted in the inner membrane and is often closely associated with the type II secretion system machinery. Mature pilins and pseudopilins have a lollipop-shaped structure, made up of a long hydrophobic tail and a globular hydrophilic head domain. Once in the periplasm in their mature state, the pseudopilins will then often be inserted into the outer leaflet of the inner membrane via their hydrophobic tails.

The major pseudopilin present in the pseudopilus is GspG. The pseudopilus forms when the individual pseudopilin subunits polymerize together. In this reaction the hydrophobic tails of different pseudopilins mesh together leaving their globular hydrophilic heads exposed. These long hydrophobic tails are able to aggregate together like this due to strong hydrophobic interactions and the end result is that the pseudopilus steadily grows. The assembly and disassembly of these pseudopilus subunits is powered by the secretion ATPase GspE. It is thought that this constant extension and retraction of the pseudopilus causes it to act like a piston and push secretory proteins out through the outer membrane secretin. When the pseudopilus then retracts new secretory proteins can then enter the system and the process will repeat. This movement of the pseudopilus is similar to the movement displayed by type IV pili which is known to enable twitching motility. [13]

Diagram showing the type II secretion system Type II secretion system.png
Diagram showing the type II secretion system

Mechanism

Secretion of proteins via the type II secretion system occurs in a very specific way and is largely uniform among different species of bacteria. This mechanism can be broken down into several steps:

  1. Exoproteins, or proteins that are to be secreted, are first transported across the inner membrane and into the periplasm via the Sec translocation machinery. These exoproteins will exist here in the periplasm secretion until the type II secretion system is activated.
  2. Pre-pseudopilins are also transported from the cytoplasm into the periplasm via the Sec translocation machinery. Once in the periplasm they are cleaved by the pre-pilin peptidase GspO and converted into mature pseudopilins. The mature pseudopilins can then insert themselves into the inner membrane where they will exist until pseudopilus assembly occurs.
  3. The secretion ATPase GspE will then bind and hydrolyze ATP and the energy produced is used to power the formation of the pseudopilus. GspE is located in the cytoplasm but remains associated with the inner membrane complex via interactions with both GspL and GspF.
  4. When activated, the exoproteins previously transported into the periplasm are able to enter the secretion machinery. It is not fully understood how these exoproteins are selected for, but it is believed the interaction between GspC and GspD plays an important role.
  5. The assembly of the pseudopilus then forces the exoproteins out through the secretin GspD and into the extracellular milieu. This secretin forms a hydrophilic channel in the outer membrane which allows the proteins to exit the cell.
  6. Once outside of the cell the secreted exoproteins can then carry out their intended effects. Some of these for instance may be involved in signalling and others may act as virulence factors that help promote infection.

It is believed that quorum sensing plays a key role in controlling the activation of the type II secretion system and the initiation of exoprotein release. [6] Specifically quorum sensing helps regulate the transcription of the genes encoding these exoproteins and ensures that they are only produced when other like bacteria are nearby and environmental conditions are conducive to survival and infection.

Related Research Articles

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

<span class="mw-page-title-main">Exocytosis</span> Active transport and bulk transport in which a cell transports molecules out of the cell

Exocytosis is a form of active transport and bulk transport in which a cell transports molecules out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive means. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

The translocon is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself. In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex are formed from Sec proteins, with the heterotrimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in gram-positive bacteria, between cell wall and the plasma membrane. The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.

<span class="mw-page-title-main">ATP-binding cassette transporter</span> Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

<span class="mw-page-title-main">Bacterial outer membrane</span> Plasma membrane found in gram-negative bacteria

The bacterial outer membrane is found in gram-negative bacteria. Gram-negative bacteria form two lipid bilayers in their cell envelopes - an inner membrane (IM) that encapsulates the cytoplasm, and an outer membrane (OM) that encapsulates the periplasm.

<span class="mw-page-title-main">Type III secretion system</span> Bacterial virulence factor

The type III secretion system is one of the bacterial secretion systems used by bacteria to secrete their effector proteins into the host's cells to promote virulence and colonisation. While the type III secretion system has been widely regarded as equivalent to the injectisome, many argue that the injectisome is only part of the type III secretion system, which also include structures like the flagellar export apparatus. The T3SS is a needle-like protein complex found in several species of pathogenic gram-negative bacteria.

Translocase is a general term for a protein that assists in moving another molecule, usually across a cell membrane. These enzymes catalyze the movement of ions or molecules across membranes or their separation within membranes. The reaction is designated as a transfer from “side 1” to “side 2” because the designations “in” and “out”, which had previously been used, can be ambiguous. Translocases are the most common secretion system in Gram positive bacteria.

In enzymology, a protein-secreting ATPase (EC 3.6.3.50) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Autotransporter family</span>

In molecular biology, an autotransporter domain is a structural domain found in some bacterial outer membrane proteins. The domain is always located at the C-terminal end of the protein and forms a beta-barrel structure. The barrel is oriented in the membrane such that the N-terminal portion of the protein, termed the passenger domain, is presented on the cell surface. These proteins are typically virulence factors, associated with infection or virulence in pathogenic bacteria.

<span class="mw-page-title-main">SecY protein</span>

The SecY protein is the main transmembrane subunit of the bacterial Sec export pathway and of a protein-secreting ATPase complex, also known as a SecYEG translocon. Homologs of the SecYEG complex are found in eukaryotes and in archaea, where the subunit is known as Sec61α.

SecD and SecF are prokaryotic protein export membrane proteins. They are a part of the larger multimeric protein export complex comprising SecA, D, E, F, G, Y, and YajC. SecD and SecF are required to maintain a proton motive force.

<span class="mw-page-title-main">Trimeric autotransporter adhesin</span> Proteins found on the outer membrane of Gram-negative bacteria

In molecular biology, trimeric autotransporter adhesins (TAAs), are proteins found on the outer membrane of Gram-negative bacteria. Bacteria use TAAs in order to infect their host cells via a process called cell adhesion. TAAs also go by another name, oligomeric coiled-coil adhesins, which is shortened to OCAs. In essence, they are virulence factors, factors that make the bacteria harmful and infective to the host organism.

Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory cell. It takes place in the form of Golgi membrane-bound micro-sized vesicles, termed membrane vesicles (MVs).

<span class="mw-page-title-main">Outer membrane vesicle</span> Vesicles released from the outer membranes of Gram-negative bacteria

Outer membrane vesicles (OMVs) are vesicles released from the outer membranes of Gram-negative bacteria. While Gram-positive bacteria release vesicles as well those vesicles fall under the broader category of bacterial membrane vesicles (MVs). OMVs were the first MVs to be discovered, and are distinguished from outer inner membrane vesicles (OIMVS), which are gram-negative baterial vesicles containing portions of both the outer and inner bacterial membrane. Outer membrane vesicles were first discovered and characterized using transmission-electron microscopy by Indian Scientist Prof. Smriti Narayan Chatterjee and J. Das in 1966-67. OMVs are ascribed the functionality to provide a manner to communicate among themselves, with other microorganisms in their environment and with the host. These vesicles are involved in trafficking bacterial cell signaling biochemicals, which may include DNA, RNA, proteins, endotoxins and allied virulence molecules. This communication happens in microbial cultures in oceans, inside animals, plants and even inside the human body.

<span class="mw-page-title-main">Twitching motility</span> Form of crawling bacterial motility

Twitching motility is a form of crawling bacterial motility used to move over surfaces. Twitching is mediated by the activity of hair-like filaments called type IV pili which extend from the cell's exterior, bind to surrounding solid substrates, and retract, pulling the cell forwards in a manner similar to the action of a grappling hook. The name twitching motility is derived from the characteristic jerky and irregular motions of individual cells when viewed under the microscope. It has been observed in many bacterial species, but is most well studied in Pseudomonas aeruginosa, Neisseria gonorrhoeae and Myxococcus xanthus. Active movement mediated by the twitching system has been shown to be an important component of the pathogenic mechanisms of several species.

<span class="mw-page-title-main">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

The bacterial type IV secretion system, also known as the type IV secretion system or the T4SS, is a secretion protein complex found in gram negative bacteria, gram positive bacteria, and archaea. It is able to transport proteins and DNA across the cell membrane. The type IV secretion system is just one of many bacterial secretion systems. Type IV secretion systems are related to conjugation machinery which generally involve a single-step secretion system and the use of a pilus. Type IV secretion systems are used for conjugation, DNA exchange with the extracellular space, and for delivering proteins to target cells. The type IV secretion system is divided into type IVA and type IVB based on genetic ancestry.

Type VII secretion systems are bacterial secretion systems first observed in the phyla Actinomycetota and Bacillota. Bacteria use such systems to transport, or secrete, proteins into the environment. The bacterial genus Mycobacterium uses type VII secretion systems (T7SS) to secrete proteins across their cell envelope. The first T7SS system discovered was the ESX-1 System.

References

  1. ↑ Douzi B, Filloux A, Voulhoux R (2012). "On the path to uncover the bacterial type II secretion system". Philosophical Transactions of the Royal Society B: Biological Sciences . 367 (1592): 1059–1072. doi:10.1098/rstb.2011.0204. PMC   3297435 . PMID   22411978.
  2. ↑ Tseng T, Tyler BM, Setubal JC (2009). "Protein secretion systems in bacterial-host associations, and their description in the Gene Ontology". BMC Microbiology . 9: S2. doi: 10.1186/1471-2180-9-S1-S2 . PMC   2654662 . PMID   19278550.
  3. 1 2 Korotkov KV, Sandkvist M, Hol WG (2012). "The type II secretion system: biogenesis, molecular architecture and mechanism". Nature Reviews Microbiology . 10 (5): 336–351. doi:10.1038/nrmicro2762. PMC   3705712 . PMID   22466878.
  4. ↑ Natale P, Bruser T, Driessen AJ (2008). "Sec- and Tat-mediated protein secretion across the bacterial cytoplasmic membrane—Distinct translocases and mechanisms". Biochimica et Biophysica Acta (BBA) - Biomembranes . 1778 (9): 1735–1756. doi: 10.1016/j.bbamem.2007.07.015 . PMID   17935691.
  5. 1 2 3 Filloux A (2004). "The underlying mechanisms of type II protein secretion". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1–3 (1–3): 163–179. doi:10.1016/j.bbamcr.2004.05.003. PMID   15546665.
  6. 1 2 Sandkvist M (2001). "Type II Secretion and Pathogenesis". Infection and Immunity . 69 (6): 3523–3535. doi:10.1128/IAI.69.6.3523-3535.2001. PMC   98326 . PMID   11349009.
  7. ↑ Craig L, Pique ME, Tainer JA (2004). "Type IV pilus structure and bacterial pathogenicity". Nature Reviews Microbiology . 2 (5): 363–378. doi:10.1038/nrmicro885. PMID   15100690. S2CID   10654430.
  8. 1 2 von Tils D, Blädel I, Schmidt MA, Heusipp G (2012). "Type II secretion in Yersinia—a secretion system for pathogenicity and environmental fitness". Frontiers in Cellular and Infection Microbiology . 2: 160. doi: 10.3389/fcimb.2012.00160 . PMC   3521999 . PMID   23248779.
  9. ↑ Korotkov KV, Gonen T, Hol WG (2011). "Secretins: dynamic channels for protein transport across membranes". Trends in Biochemical Sciences . 36 (8): 433–443. doi:10.1016/j.tibs.2011.04.002. PMC   3155655 . PMID   21565514.
  10. ↑ Ricci DP, Silhavy TJ (2012). "The Bam machine: A molecular cooper". Biochimica et Biophysica Acta (BBA) - Biomembranes . 1818 (4): 1067–1084. doi:10.1016/j.bbamem.2011.08.020. PMC   3253334 . PMID   21893027.
  11. ↑ Johnson TL, Abendroth J, Hol WG, Sandkvist M (2006). "Type II secretion: from structure to function". FEMS Microbiology Letters . 255 (2): 175–186. doi: 10.1111/j.1574-6968.2006.00102.x . hdl: 2027.42/74575 . PMID   16448494.
  12. 1 2 Lu C, Turley S, Marionni ST, Park SY, Lee KK, Patrick M, Shah R, Sandkvist M, Bush MF, Hol WG (2013). "Hexamers of the Type II Secretion ATPase GspE from Vibrio cholerae with Increased ATPase Activity". Structure . 21 (9): 1707–1717. doi:10.1016/j.str.2013.06.027. PMC   3775503 . PMID   23954505.
  13. ↑ Mattick JS (2002). "Type IV pili and twitching motility". Annual Review of Microbiology . 56: 289–314. doi:10.1146/annurev.micro.56.012302.160938. PMID   12142488.
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