View source for Lengsin


<Structure load='2j9i' size='350' frame='true' align='right' caption='Mouse penguin (PDB code [[2j9i]]).' scene='' />


=='''Introduction'''==

'''Glutamine Synthetase:'''

<scene name='83/837873/Lengsin/5'>Lengsin</scene> (2J9I), is a protein associated with structural formation of the eye. Lengsin has evolutionary relation to <scene name='83/837873/Human_glutamine_synthetase/2'>Glutamine synthetases</scene>, which gives rise to the term lengsin (LENs Glutamine SYNthetase). This protein is specifically classified as a Glutamine Synthetase I, a part of the Glutamine synthetase superfamily. Glutamine synthetases are most well known for their presence in the urea cycle, where they detoxify nitrogen in the body. In other words, Glutamine Synthetases fixate ammonium and create glutamine mechanistically through the utilization of adenosine triphosphate (ATP) and help make the metabolic processes happen. Despite its close relation to this class of enzymes, lengsin, however, does not have any enzymatic activity, and is, therefore, not necessarily metabolic.<ref name=ref1>PMID:Grassi , F. J., Moretto, N. J., Rivetti, C. J., Cellai, S. J., Betti, M. J., Márquez , A. Ontonello, S. J. (2006). Structural and Functional Properties of Lengsin, a Pseduo-Glutamine Synthetase in the Transparent Human Lens . Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/173917.pdf</ref>
In fact, no catalytic function was present in multiple assays. lengsin was, therefore, declared a noncatalytic dodecamer. Possible reasons for the lack of activity in lengsin could relate to the binding of NH4+ and ATP to the protein, or its inflexibility when transforming to an oligomeric form. Moreover, this protein was first found in a house mouse (''mus muluscus'') via electron microscopy, and it has been found to have been an important <scene name='83/837873/Evoluntionary_conservation/1'>evolutionary stepping stone</scene> in the formation of the eye lens in several vertebrate species.<ref name=ref1>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref>
Studies have revealed that the evidence for Lengsin’s evolutionary significance lies within the genes which code for this protein. In the N-terminal domain, lies specific exons <ref name=ref2>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref>. Through studying the removal and addition of these exons in multiple species, scientists discovered an inactive exon (pseudoexon) in humans which points to clear evolutionary evidence. In many other non-mammalian species, this exon still provides relevance to their overall genome. However, in humans, the pseudoexon is nothing but an extra bit of genetic coding with no known genetic value. For example, comparisons done in fish and birds revealed the activity of multiple exons, including the exon in the n-terminal domain. However, the comparative lengths and numbers  of the exons did change within species. <ref name=ref2>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref> The most commonly researched Lengsin dependent species are birds, mice, and fish. Research found that lengsin in zebrafish is about 3,000 base pairs, composed of 4 exons, located on chromosome 11 in the zebrafish embryos. In contrast, mammalian lengsin is approximately 5 exons, located on chromosome 6, so it only shares about 40% genetic similarity to mice and human versions of the protein. <ref name=ref1>PMID:Grassi , F. J., Moretto, N. J., Rivetti, C. J., Cellai, S. J., Betti, M. J., Márquez , A. Ontonello, S. J. (2006). Structural and Functional Properties of Lengsin, a Pseduo-Glutamine Synthetase in the Transparent Human Lens . Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/173917.pdf</ref>  Nonetheless, this protein performs significant tasks in vertebral species by modifying and creating the structure of the lens as well as executing some other specific functions.

=='''Structure & Function'''==
'''Structure:'''

Lengsin protein structure varies depending on the species in which it is presented due to the varying genetics within species. For example, in humans the n-terminal domain is the biggest indication that Lengsin contributes to the formation of the eye via evolution. This polymer consists of 421 residues composed of primarily <scene name='83/837873/Structural_composition/3'>alpha helix residues (140 residues) and 79 Beta Sheets</scene>. It is approximately 17  Angstroms in length and has a D<sub>6</sub> Dihedral globular symmetry.<ref name=ref5>PMID:RCSB Protein Data Bank. (n.d.). PBD Structure. Retrieved from http://www.rcsb.org/pdb/explore/remediatedSequence.do;jsessionid=CD7F39FC7BF568D64508042AF64E04A0?structureId=2J9I¶</ref> A D<sub>6</sub> symmetry constitutes 6 points of rotation and reflection across the Dihedral symmetry axis. It also has twelve Glutamate-ammonia ligase proteins. <scene name='83/837873/Hydrophobic_areas_of_lengsin/1'>Lengsin is generally neither highly hydrophobic, nor highly hydrophilic</scene>. Although, it does have certain hydrophobic binding sites used for interaction with other hydrophobic molecules during lens formation. In total, there are six binding sites on lengsin which contribute to lens formation.<ref name=ref1>PMID:Grassi , F. J., Moretto, N. J., Rivetti, C. J., Cellai, S. J., Betti, M. J., Márquez , A. Ontonello, S. J. (2006). Structural and Functional Properties of Lengsin, a Pseduo-Glutamine Synthetase in the Transparent Human Lens . Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/173917.pdf</ref> These proteins are found in a several vertebrate species (and even in some prokaryotes although the function is unclear). 

'''Function:'''

Lengsin’s overall role is to help participate in the formation of the lens during the cellular development of vertebrates. However, its discovery is a relatively recent addition to modern science, so researchers have not found the exact function of this protein. Although, there is some general knowledge of the overall functions and contributions of this protein, there are only guesses as to what the specific cellular contributions could be. Two schemes can overview the likely function of the protein lengsin: an aid in deamination or a chaperone protein. Since lengsin is classified as a Glutamine Synthetase, it could theoretically fix ammonia. There are several proposed functions of lengsin’s nitrogen fixation, however. With this, conversely, lies a predicament. The missing link in this proposal is that vertebrate eyes contain another sub type of Glutamine Synthetases assocoated with the urea cycle that fixes ammonia prior to lengsin. So, the prospective thought process behind this mechanism is the tissue is inefficient at fixing the ammonia within the urea cycle, and needs aid via lengsin. Thus, lengsin would need to be present for complete removal of ammonia.  In fact, crystalline structures help to prove this. It is thought that the deamination requires an enzyme with an asparagine and glutamine side chains to assist deamination. A different suggestion that was made was that the function of lengsin was to chaperone the formation of the lens.The overall structure of Lengsin in humans is wildly similar to other crystalline chaperone proteins.  <ref name=ref2>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref> Finally, Lengsin is capable of being deactivated by the <scene name='83/837873/Amyloid_beta_protein/1'>amyloid-Beta protein</scene> which is, interestingly enough, a well known binding protein associated with Alzheimer's disease.<ref name=ref1>PMID:Grassi , F. J., Moretto, N. J., Rivetti, C. J., Cellai, S. J., Betti, M. J., Márquez , A. Ontonello, S. J. (2006). Structural and Functional Properties of Lengsin, a Pseduo-Glutamine Synthetase in the Transparent Human Lens . Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/173917.pdf</ref>

=='''Research'''==

'''I. Zebrafish:'''

Around one day after fertilization, the zebrafish begins to develop. Among the first appendages to form is the lens of this aquatic creature’s eye, fabricated by Lengsin mechanistically. Within the zebrafish study, lengsin from zebrafish embryos was mixed with rabbit polyclonal antiserum via a bacterial fusing protein. This portion of the study revealed the suggestion that the protein cleaves itself upon maturation, due to the decreased length in correlation to age. This, in turn, decreases the protein concentration in adult fish. This could be because lengsin’s role is to differentiate cell types during embryo development. So, it is less useful to fully grown zebrafish. In this way, in mature zebrafish, this protein cannot be detected in any other tissues but the lens.<ref name=ref3>PMID:Harding, R. L., Howley, S., Baker, L. J., Murphy, T. R., Archer, W. E., Wistow, G., … Vihtelic, T. (2008). Lengsin expression and function during zebrafish lens formation. Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/</ref>

'''II. Human Eye:'''

Unlike zebrafish, adult humans appear to have high levels of lengsin in the eye.In fact, it is one of the most abundant, non-crystallized proteins present in the human lens. <ref name=ref1>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref> However, one exception does apply: cataracts. If cataracts are present, lengsin levels are low <ref name=ref1>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref>. Therefore, it is believed that this protein is crucial in not only lens formation, but maintaining stability and transparency of the human eye as well. Furthermore, this could be why elderly patients are most prone to cataracts, due to the maturation of the eye causing loss of lengsin, which results in a less structurally sound lens.
In homo sapiens, the gene for this protein is found on chromosome 6. 
While this is different from zebrafish, another contrast between the two species of lengsin is the presence in the body. While zebrafish were found to have lengsin specifically in the eyes, humans have some small amounts of lengsin in other tissues as well (under specific circumstances) .<ref name=ref1>PMID:Wyatt, K., White, H. E., Wang, L., Bateman, O. A., Slingsby, C., Orlova, E. V., & Wistow, G. (2006). Lengsin is a survivor of an ancient family of class I glutamine synthetases re-engineered by evolution for a role in the vertebrate lens. Structure (London, England : 1993), 14(12), 1823–1834. https://doi.org/10.1016/j.str.2006.10.008</ref> Thus, this protein serves multiple functions in humans.

'''III. Tumor Antigen:'''

Although there is still research being conducted on it, lengsin appears to have numerous, important roles in the mature human body. In fact, this protein has also been reported as a known tumor antigen, and it most specifically has been associated with lung cancers. 
Studies from 2011 revealed that high levels of lengsin are present in the entire spectrum of lung cancer classifications. This is unusual because lengsin is most prominently found in the lens. In fact, in lung cancer patients, it has been observed that lengsin levels are elevated. This information is an essential clue to how to treat lung cancers. Using protein derivatives, specified antigens care can be given to carcinoma patients. For example, lengsin is a highly specific solution to lung cancers due to the body’s natural response. In treatment, lengsin can be spliced to help suppress tumors, and perform its antigenic function. Since these cancer cells naturally produce lengsin, the protein can be extracted from the surface of the lymphocyte cells. This also allows for easy binding of the cancer treatment via antigens. In this study, several variations of the protein were explored, and there were some that had higher success rates than others. It is, nonetheless, crucial to note that these studies were performed on mice, so the success rates are species specific. There is not much research supporting evidence that lengsin would be efficient at treating other types of cancers.<ref name=ref4>PMID: Nakatsugawa, M., Horie, K., Yoshikawa, T., Shimomura, M., Kikuchi, Y., Sakemura, N., … Nakatsura, T. (2011). Identification of an HLA-A*0201-restricted Cytotoxic T Lymphocyte Epitope from the Lung Carcinoma Antigdn, Lengsin. Retrieved from https://maryville.illiad.oclc.org/illiad/pdf/</ref>





=='''References'''==
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