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Characterizing ASXL3

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Characterzing ASXL3 Leah Buck & Chloe Carroll University of North Alabama [email protected] [email protected] Abstract Results In this study ASXL3 ser2214pro mutation was examined using virtual structural assessment and analysis of previous research in order to better understand what effects a mutation in the gene sequence of ASXL3 would have The conclusions obtained through the study are based around the idea of the zinc finger structure on the structure and function of the protein. The main structure generating software used was YASARA (Yet An- in ASXL3, its stability, and the amino acid changes that would have a destabilizing impact on its other Scientific Artificial Reality Application). A model for the wild type ASXL3 and the mutated ASXL3 were generated using YASARA (Krieger, 2014). Models from I-Tasser and Uniprot were created and compared using conformation. Through structural modeling, it was found the mutation of Serine to Proline at the the YASARA homology modeling tool. Various models were used to further examine the effects of the mutation on 2214th position in ASXL3 may have an effect on the overall protein structure (Fig.1). In I-Tasser the structure. A molecular simulation was carried out to assess the changes a mutation would have in this domain, models,it can be seen that the important ligand, Zinc, is not present. When aligned with the original and gain corresponding data. The function of ASXL3 was examined using the Allen Brain Atlas and examination ASXL3 PHD model, the RMSD value was 0 and there was no sequence identity. This was most likely of mouse gene knockout studies. The comparison of these models shows that the mutation in ASXL3 affects the because the zinc atom is present in the original model, not the I-Tasser model and is necessary for structural integrity of the protein as well as presence in certain areas of the brain (Fig. 1). the overall structure of the domain being analyzed. Previous research has found that the mutation prevents the attachment of the zinc finger within the protein because of the cyclic structure of proline which creates a more rigid bond than serine. When a mutation is present, the zinc finger is not at- Introduction tached, and the section of the protein containing it is allowed to move freely causing the protein the be less structurally sound and to be less condensed. The the wild type ASXL3 is much more stable than that of the mutated gene. Its radius of gyration has a smaller range of motion than the mutated Variables of uncertain significance (VUS) are an intriguing problem in the field of genetic biotechnol- form, leading to the assumption that the mutated form is more mobile, despite the proline mutation ogy. As most genetic sequencing brings back relatively small amounts of actionable information, it is that causes a more rigid bond (Fig. 3). Analysis of information provided by the Allen Brain Atlas imperative to delve into VUS in an attempt to find big answers to the smallest problems and mutations indicated moderate levels of ASXL3 expression in both the Anterior Cingulate Cortex (ACC) as well within the genome. ASXL3 is a gene that codes for a transcription-regulator protein. It is a type of as the Primary Visual Cortex (PVC), values of which can be seen in figure 2. This suggests that a RNA polymerase that contains a zinc finger domain (the PHD domain). The zinc finger domain is a mutation in the PHD domain of ASXL3 may be the cause of certain aforementioned developmental polypeptide chain surrounding a zinc atom that serves to stabilize the fold, and is significant, in that diseases. Higher levels of expression of ASXL3 was shown in the ACC, than PVC. The differences it is found commonly in regulatory proteins. ASXL3 has demonstrated involvement in the negative discussed above support the conclusion that the mutation of serine to proline at the 2214th position regulation of lipogenesis by binding to and inhibiting transcriptional hormone receptors, those be- of ASXL3 may have an effect on the structure of ASXL3. The data that lead to these conclusions ing the oxysterol receptors, and thyroid hormone receptors.(NCBI, 2019) The protein encoded also indicates that the mutation in question may have significant loss of function properties, and may be inhibits histone deubiquitination. The consideration of the stabilizing and regulatory aspects of this the cause of certain diseases in correlating regions of the brain. gene lends to the idea that a mutation in this domain would be debilitating. Previous evidence in- dicates mutations in this region may be linked to Bainbridge-Ropers and Bohring Opitz syndromes, both of which correlate to developmental delays, learning disabilities, and failure to thrive. The muta- tion in the selected VUS is a serine to proline missense mutation at the 2114 position. It is significant because of the nature of the amino acid proline and its effect on bending of polypeptide chains. The mutation is almost certainly a loss of function mutation. Methods Figure 3: Graphical representation of radius of gyration from molecular dynamic simulation An initial wild type protein model of ASXL3 (Huret et al., 2013) was used as a baseline for model- ing and comparison, and the mutated form was first modeled using the computer program YASARA (Krieger, 2014) by substituting serine for proline using the swap residue function. (Fig. 1). A second structure of ASXL3 was created using data from I-Tasser (Yang et al, 2015), in which it was neces- Conclusions sary to split the sequence due to size. This returned a flawed model, so the process was repeated to produce a better model, that was then aligned with the original model from Prokop (2018). A third • The mutation may alter the function and folding of the protein. structure of ASXL3 was created via slow and fast homology modeling. A fourth round of structures • ASXL3 is exhibits significant expression in regions of the brain such as Primary Visual Cortex and of ASXL3 were modeled via molecular simulation in YASARA. Gene knockout studies of ASXL3 Anterior Cingulate Cortex were examined to identify areas of the body that are affected by the removal of ASXL3. If affected • The mutation in question is almost certainly damaging. the region is not functional this indicates that the cells in this area are able to produce ASXL3 and ASXL3 has a function within that region. The Allen Brain Atlas was used to study the types of cells that exhibit ASXL3, and would thus be affected by the mutation, and were used to examine the areas of the brain that contain the ASXL3 protein to find correlations between the phenotype expressed due Forthcoming Research to the mutation and the areas of the brain affected. STRING database (Szklarczyk et al, 2017) was We plan to continue to organize and interpret the information from the Allen Brain Atlas specifically used to find corresponding genes and gene families related to ASXL3. Of particular interest were identifying the cell types affected. We want to determine if the cell types associated with ASXL3 and ASXL 1 and 2 and BAP1. Both ASXL3 and BAP1 are transcription regulators. its associated proteins are also associated with the phenotype of patient with mutation in question. References 1. Allen Human Brain Atlas Hawrylycz, M.J. et al. (2012) An anatomically comprehensive atlas of the adult human transcriptome, Nature 489: 391-399. doi:10.1038/nature11405 2. ASXL3. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2018 [cited 11/12/2018]. Available from: https://www.ncbi.nlm.nih.gov/gene/80816 3. E. Krieger, G. Vriend. YASARA view molecular graphics for all devices from smartphones to workstations Bioinformatics., 30 (2014), pp. 2981-2982, 10.1093/bioinformatics/btu426 4. J Yang, R Yan, A Roy, D Xu, J Poisson, Y Zhang. The I-TASSER Suite: Protein structure and function prediction. Nature Methods, 12: 7-8 (2015).85 5. Prokop, J. PhD. (2018, October). Interview type [Online Video Messaging]. Figure 1: Wild type ASXL3 (left) mutated ASXL3 (Right) structure created using YASARA . 6. National Center for Biotechnology Information; ASXL3 ASXL3 transcriptional regulator 3 [Homosapiens (human)]-Gene-NCBI,April 15, 2019, date accessed: April 18, 2019, https://www.ncbi.nlm.nih.gov/gene/80816 7. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C.The STRING database in 2017: quality-controlled protein- protein association networks, made broadly accessible. Nucleic Acids Res. 2017 Jan; 45:D362- 68.PubMed 8. The UniProt Consortium; UniProt: the universal protein knowledgebase, Nucleic Acids Research. https://doi.org/10.1093/nar/gkw1099 Acknowledgements Figure 2: Level of average expression of ASXL1, ASXL2, ASXL3 and BAP1 in Anterior Cingulate Cortex (left) versus Primary Visual Cortex (right). Faculty Mentors: Dr. Cynthia Stenger and Dr. Jillian Stupiansky. Special thanks to Dr. Jere- mey Prokop, Prokop Labs, Michigan State University and David Hinds, HudsonAlpha Institute for Biotechnology..
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