This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
Protein Interaction Networks
Protein interaction networks are diagrams showing the proteins that one specific protein interacts with. These interactions can be primary (direct) interactions or secondary (indirect, with a primary protein as an intermediate). Protein interaction networks can be used to glean information about not only the interactions of a protein but also the biological processes that a protein affects.
TOP3β Protein Interaction Networks
To the left is a diagram of the protein interaction network of TOP3B (click to enlarge). The interacting proteins have been grouped based on their functions and associations. This network was created in STRING, an online database of known and predicted protein interactions. These interactions are derived from four sources: genomic context (such as sequence), high-throughput experiments, conserved coexpression, and previous knowledge [1]. I simply typed in TOP3Beta into the search bar and then pressed the '+' button once when the network image appeared, allowing me to see secondary interactions as well as primary ones. STRING is also great because the program allows you to move the protein icons around in the image and provides information about each protein, that is how I was able to create the groups.
Analysis of the TOP3β Protein Network
Two recent studies found that TOP3β can bind both RNA and other proteins [2]. One of the proteins found to interact with TOP3β was FMRP, a protein that binds mRNA and represses translation. The other protein was TDRD3, with is suggested to play a role in the formation of RNA stress granules [2]. RNA stress granules are clumps of RNA that form when the cell is under stress [3]. Furthermore, TOP3β was also found to localize to cytoplasmic compartments containing specific RNAs following cellular stress [2]. All of these findings led me to suspect that when I searched for the protein interaction network for TOP3β, I would find proteins involved in RNA regulation and the stress response.
The green section of the protein network is not surprising at all; the best known function of TOP3β is binding to DNA and changing its topology. The purple circle that includes proteins involved in ubiquitination (ubiquitin is a chemical tag that can be added to proteins and RNAs to mark them for degradation) could be seen as falling under my hypothetical category of RNA regulation [4]. While I did not retrieve any results of proteins specifically labeled as being involved in the stress response, lipid levels are related to stress responses [5]. Thus, the blue circle could be seen as falling under the stress response category. Another study has also recently proposed polyunsaturated fats as preventative measures or a treatment for schizophrenia [6], making this finding even more compelling. Certainly the role of protein binding (red circle) was not surprising either due to these recent findings. The role that I had not thought of before turning to STRING was signaling (black circle). However, it makes sense. Schizophrenia is a complex brain disorder, with symptoms relating to communication issues, learning issues, and the inability to discern real from imagined. It is very logical that faulty signaling could be the behind all of these symptoms. Thus, TOP3β being found to interactive with proteins involved in signaling actually makes a lot of sense.
The green section of the protein network is not surprising at all; the best known function of TOP3β is binding to DNA and changing its topology. The purple circle that includes proteins involved in ubiquitination (ubiquitin is a chemical tag that can be added to proteins and RNAs to mark them for degradation) could be seen as falling under my hypothetical category of RNA regulation [4]. While I did not retrieve any results of proteins specifically labeled as being involved in the stress response, lipid levels are related to stress responses [5]. Thus, the blue circle could be seen as falling under the stress response category. Another study has also recently proposed polyunsaturated fats as preventative measures or a treatment for schizophrenia [6], making this finding even more compelling. Certainly the role of protein binding (red circle) was not surprising either due to these recent findings. The role that I had not thought of before turning to STRING was signaling (black circle). However, it makes sense. Schizophrenia is a complex brain disorder, with symptoms relating to communication issues, learning issues, and the inability to discern real from imagined. It is very logical that faulty signaling could be the behind all of these symptoms. Thus, TOP3β being found to interactive with proteins involved in signaling actually makes a lot of sense.
References
[1]. STRING-Known and Predicted Protein-Protein Interactions. version 9.1. retrieved Apr. 11, 2014. http://string-db.org/newstring_cgi/show_input_page.pl?UserId=uX7KleQVTgGs&sessionId=gCTdFxy6JQaO
[2].Nott, A. The TOP3B way to untangle RNA. Nat. Neurosci. 2013 Sep: 16(9):1163-64.
[3]. Kayali F, Montie HL, Rafols JA, DeGracia DJ. Prolonged translation arrest in reperfused hippocampal cornu Ammonis 1 is mediated by stress granules. 2005. Neuroscience 134 (4): 1223–45. doi:10.1016/j.neuroscience.2005.05.047. PMID 16055272.
[4]. wiseGEEK. What is Ubiquitination? retrieved Apr 16, 2014. http://www.wisegeek.com/what-is-ubiquitination.htm
[5]. Wirtz PH. et. al. Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Metabolism. 2009 Jan;58(1):30-7. doi: 10.1016/j.metabol.2008.08.003. http://www.ncbi.nlm.nih.gov/pubmed/19059528
[6]. Hashimoto, M. et. al. Possibility of polyunsaturated fatty acids for the prevention and treatment of neuropsychiatric illnesses. J Pharmacol Sci. 2014 Mar 18; 124(3):294-300. Epub 2014 Feb 22. PMID: 24561447
[2].Nott, A. The TOP3B way to untangle RNA. Nat. Neurosci. 2013 Sep: 16(9):1163-64.
[3]. Kayali F, Montie HL, Rafols JA, DeGracia DJ. Prolonged translation arrest in reperfused hippocampal cornu Ammonis 1 is mediated by stress granules. 2005. Neuroscience 134 (4): 1223–45. doi:10.1016/j.neuroscience.2005.05.047. PMID 16055272.
[4]. wiseGEEK. What is Ubiquitination? retrieved Apr 16, 2014. http://www.wisegeek.com/what-is-ubiquitination.htm
[5]. Wirtz PH. et. al. Changes in plasma lipids with psychosocial stress are related to hypertension status and the norepinephrine stress response. Metabolism. 2009 Jan;58(1):30-7. doi: 10.1016/j.metabol.2008.08.003. http://www.ncbi.nlm.nih.gov/pubmed/19059528
[6]. Hashimoto, M. et. al. Possibility of polyunsaturated fatty acids for the prevention and treatment of neuropsychiatric illnesses. J Pharmacol Sci. 2014 Mar 18; 124(3):294-300. Epub 2014 Feb 22. PMID: 24561447