Trimeric autotransporter adhesin

Most TAAs have a similar protein structure. When observed with electron microscopy, the structure has been described as a "lollipop" shape consisting of an N-terminal head domain, a stalk domain, and a C-terminal membrane anchor domain. ==Extended Signal Peptide Region domain==

The Extended Signal Peptide Region (ESPR) is found in the N-terminus of the signal peptides of proteins belonging to the Type V secretion systems. The function of the ESPR is to aid inner membrane translocation by acting as a temporary tether. This prevents the accumulation of misfolded proteins. The ESPR can be divided into individual regions, they are as follows: N1 (charged), H1 (hydrophobic), N2, H2 and C (cleavage site) domains. N1 and H1 form the ESPR and have strong conservation. Function: There are several roles that the Extended Signal Peptide Region is thought to hold. First, biogenesis of proteins in the Type V Secretion System (T5SS). Second, it is thought to target the protein to the inner membrane to be translocated either by the signal recognition particle pathway (SRP) or by twin arginine translocated (TAT). Third, it has been observed and believed to regulate the rate of protein migration into the periplasm. ==N-terminal head domain==

Structure: This particular domain is a trimer of single-stranded, left-handed beta-helices. These associate to form a nine-coiled left-handed beta-roll. It contains sequence motifs, of which there is a strong similarity with other TAA heads. This indicates that there is a lot of similarity when comparing protein structure. The head domain is connected to the stalk by a short, highly conserved sequence, which is often called the neck, or occasionally named the connector. The head domain is very important for attachment to the host cell and for autoagglutination, sticking to itself. (Figure used from open access journal, in the public domain, Public Library of Science (PLoS) Pathogen) There are several types of head domain. Each domain helps the head to bind to a different component of the extracellular matrix. These are as follows: YadA-like head domain, Trp-ring, GIN, FxG, HIN1, and HIN2. This entry focuses on the first three mentioned. YadA-like head YadA-like head is composed of single-stranded, left-handed beta-helices, which associate further to create a nine-coiled left-handed parallel beta-roll (LPBR). It is the tightest beta-roll structure known, and the first to be discovered. The YadA head domain has eight repeat motifs, each fourteen residues in length. Trp ring The Trp ring is the second-most-common TAA head. Trp is an amino acid named tryptophan. The Trp ring obtains its name from the high levels of tryptophan found in the C-terminal part of the Head domain. These work by stabilising the transition between the coiled-coil and the beta-meander where the head meets the neck or stalk. In many cases, the Trp ring is often followed by the GIN domain. GIN The GIN domain is a head domain named after its sequence motif GIN (Glycine-Isoleucine-Asparagine) motif. It has an all-beta structure, whereby the two pairs of antiparallel beta sheets are connected by a diagonally running extended beta-sheet. The sheets then further fold to form a beta prism in which each wall is composed of a complete set of five beta-strands. The GIN domain is often followed by a neck domain. ==Neck domain==

Structure: The neck domain is a homotrimer, where three of the same subunits associate. All three subunits are arranged in such a way that they resemble a "safety pin"-like structure.) or much shorter, unfolded (ISneck 2) perturbation. ==Stalk domain==

Structure: These domains are fibrous and found in highly repetitive numbers. They contain coiled coils and their length tends to vary among different species. The coiled-coil segments of the stalk domains have two unusual properties: ::# they alternate from right-handed to left-handed supercoiling ::# often interrupted by small globular domains, which owes to their appearance of segmented ropes. From a deeper structural perspective, coiled-coil arranges itself in such a way that the crossing angle between the helices is almost zero. The packing of these helices follows a "knobs-into-holes" arrangement whereby hydrophobic residues protrude forming knobs that pack into cavities formed by other residues on another helix. Then, once the knobs are packed into cavities, the three helices are wound in register around each other, so all of the residues in certain positions are at the same height. There are two types of stalk domain: the FGG domain and the right-handed stalk domain. ==C-terminal membrane anchor domain==

Structure: The structure of this protein domain is a left-handed coiled-coil followed by four transmembrane beta strands. It is thought that, once trimerisation has occurred, these beta strands further fold into a 12-stranded beta-barrel. It also contains a recognition site for signal peptidases, which means the enzyme will recognise the signal peptide and cleave it at a particular point. ==Model proteins==

All Trimeric Autotransporter Adhesins are crucial virulence factors that cause serious disease in humans. The most-studied and well-known Trimeric Autotransporter Adhesins are listed below: Like other TAAs, YadA also undergoes homotrimerisation to form a stable collagen-binding protein. Studies have shown that the globular N-terminal head domain of NadA is vital for adhesion. NadA also contains a coiled-coil region and also a C-terminal membrane anchor. This protein can cause pneumonia and some strains cause meningitis and sepsis. Hia has a slightly unusual N-terminal head made of beta-prisms. The beta-prism is an unusual type of protein architecture first described by Chothia and Murzin. As the name suggests, it holds three beta sheets arranged in a triangular prism and contains internal symmetry. Additionally, the head domain contains 5 Trp-Ring domains. Furthermore, this protein also contains three neck domains, of which two are IsNeck domains in addition to other domains such as KG, GANG, and TTT domains. BadA protein The BadA protein is another example of a TAA found in Bartonella henselae bacteria. Bartonella henselae is the causative agent of cat scratch disease, a normally harmless disease, but, in people with a weakened immune system, such as those undergoing chemotherapy or fighting AIDS, it is more serious as it can lead to bacillary angiomatosis. The head domain of BadA is more complex than other TAAs. It is thought to be a chimera or, in other words, a combination of YadA and Hia head domains. This combination gives insight into how the pathogenicity of Gram-negative bacteria has evolved over time. BadA also contains a neck domain, an extended coil-coil stalk, and beta-barrel C terminal membrane anchor. ==Clinical effects==

The process of infection is complicated. The invasive bacterium must overcome many barriers in order to infect its host, including environmental barriers, physical barriers and immune system barriers. The bacterium must enter the host's body and, in the case of Yersinia sp., invade the host intestinal mucosa. Then the Trimeric Autotransporter Adhesin must adhere to the layer of cells found on the internal surface, the epithelial cells, in the intestine by using its head to bind to proteins found in the extracellular matrix such as collagen, laminin, and fibronectin. ==Type V secretion system (T5SS)==

System. Secretion is one method of transferring substances across the bacterial outer membrane. Gram-negative bacteria have very different cell wall structures in comparison to Gram-positive bacteria. Gram-negative bacteria have three layers: The innermost layer is named the inner membrane; the middle layer, named the periplasmic space, is a space containing a thin layer of peptidoglycan; and the third layer is named the outer membrane, which contains lipopolysaccharides. Trimeric Autotransporter Adhesins use a particular secretion pathway, named type V secretion system (T5SS). Gram-negative bacteria must secrete adhesins, since they have an outer membrane that makes it hard for them to stick to and infect the host. The outer membrane is useful, as it allows the bacteria to colonize, and adds another layer of protection. However, the outer membrane is a barrier for the secretion of proteins, and it requires energy to transport proteins across the outer membrane. Hence, the T5SS pathway overcomes this problem. in other words, by itself. The Sec-dependent system is divided into three pathways. TAAs are one of those pathways and also go by the name type Vc secretion pathway. The mechanism is split into two. First, the protein must move across the inner membrane or, in other words, translocate, in a Sec-dependent manner via the periplasm. The signal peptide on the N-terminus acts as a temporary tether to hold it in place. Next, it must move to the outer membrane. The trimerisation aids translocation, and no translocation would occur without its beta-barrel membrane anchor. The type V secretion system is described as non-fimbrious, meaning that the bacterial cells do not use long physical appendages named pili to attach to one another. ==Evading the host's immune system==

The TAAs can help prevent the bacteria from being destroyed by the host's immune system. In particular in the case of certain Yersinia spp., the TAA YadA has a role in autoagglutination, serum resistance, complement inactivation, and phagocytosis resistance. All of these methods prevent the bacteria from being eliminated by the host and ensure its survival. ==References==