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Technical Sessions 2021 NOBCChE National Conference September 18, 2021 TECHNICAL SESSIONS Biochemistry/Biophysics 11:15 AM - 12:15 PM Collagen deposition during diabetic kidney disease enhances cellular communication (76) Haryana Thomas, Research Assistant, Chemical and Biological Engineering, University at Buffalo SUNY Diabetes is a significant burden on public health in the U.S. and worldwide. In the year 2015, over 400 million people were diagnosed with diabetes worldwide. One-third of these diabetic patients are expected to develop diabetic kidney disease, the leading cause of kidney failure. Our lack of understanding of how diabetic kidney disease progresses and affects cellular and tissue function has contributed to our inability to mitigate the rapidly rising burden of diabetic kidney disease. Excess collagen deposition is a hallmark of diabetic kidney damage, however, its impact on cellular and tissue function is still not well understood. Thus, our aim is to use a modeling approach to fill this gap in knowledge. During diabetic kidney damage, the collagen deposition that occurs in the mesangium changes the transport property of the matrix, and, therefore, the ability of signaling molecules to traverse through that medium. The extent to which collagen deposition impacts the ability of glomerular cells to communicate has not been previously investigated. Using established models, we investigated whether collagen deposition impacts glomerular cell communication. We hypothesize that the pathological deposition of collagen decreases the ability of glomerular cells to communicate. Our model predicted that collagen deposition enhances the signaling range of the mesangial cell. This enhancement can disrupt the controlled, localized inter-cellular signaling that occurs in health and thus contribute to the exacerbation of diabetic kidney damage. The novel insight gained from this mathematical study enhances our understanding of how pathological tissue damage induced by diabetes contributes to the disruption of cellular function. Key Words: Diabetic Nephropathy, Fibrosis, Transport, Cell-cell signaling Technical Sessions Biochemistry/Biophysics 1 2021 NOBCChE National Conference September 18, 2021 Regulation of MKP7 Functionality via Novel Allosteric Site (16) Ms. Shanele Shilingford, Chemistry/Chemical Biology, Yale university The dual-specificity phosphatases (DUSPs) responsible for the downregulation of the mitogen-activated protein kinases (MAPKs), are designated as the MAPK phosphatases (MKPs). MAPKs are a group of serine/threonine kinases that play important roles in cell proliferation, death, and migration. Due to their involvement in key cell functions, aberrant signaling of the MAPKs are associated with a wide range of diseases. Therefore, MKP inactivation of these kinases are vital in maintaining cellular homeostasis. The MKPs are a group of 11 catalytically active members with a somewhat conserved N-terminal and a highly conserved c-terminus catalytic domain. Catalytic activity of the MKPs have been exclusively linked to their active site cysteine and neighboring residues that facilitate MAP kinase dephosphorylation in the catalytic domain. However, we have discovered in the DUSP16, MKP7, a novel allosteric site that affects MKP7 activity. MKP7 preferentially dephosphorylates the MAPKs, JNK>>p38>ERK and is capable of trapping JNK and p38 in the cytoplasm to prevent activation of their downstream targets. Mutation of a key tyrosine (Y271) residue at this allosteric site has had a demonstrable effect on MKP’s catalytic activity. In vitro experiments using the catalytic domain of MKP7, as well as overexpression of the full- length protein in COS-7 cells show diminished activity of MKP7 Y271A, Y271S, Y271W compared to wild-type on the MAPKs JNK1/2 and p38-α. Not only is catalytic activity affected, but MKP7’s binding efficiency to JNK1/2 and p38-α is reduced when Y271 is mutated. Differences in binding affinity, encouraged us to investigate any effect Y271 has on MAPK localization and interestingly, a greater accumulation of nuclear JNK and p38 is observed in the presence of Y271 mutants compared to wild-type protein. These results provide greater insight into MKP7 interactions with MAP kinases, as well as a potential target site for small molecule therapeutics on MKP7. Key Words: Chemical Biology Assessing L-Carnitine efficacy in Chronic Chagas Disease (CD): Insights to novel treatments of CD (44) Danya A. Dean, Graduate Research Assistant, Chemistry and Biochemistry, University of Oklahoma Chagas Disease (CD) is a parasitic disease caused by Trypanasoma cruzi (T. cruzi). It is endemic to the Americas, with 6-7 million people infected worldwide and 300,000 infected in the USA. CD occurs in two stages, an acute stage with mild or no symptoms including fever and rashes, and a chronic stage which produces severe cardiac symptoms. Treatment for CD utilizes the antiparasitic benznidazole. However, it has severe side effects and low efficacy in the chronic stage of infection, due to low parasitemia. Therefore, there is a need for novel treatments for CD. We have already demonstrated the efficacy of l-carnitine as a novel treatment for acute CD. We determined that mice infected with T. cruzi had an increase in overall survival rate when treated with l-carnitine. Based on this study, we sought to investigate the efficacy of l-carnitine treatment in the chronic stage of T. cruzi infection. However, l- Technical Sessions Biochemistry/Biophysics 2 2021 NOBCChE National Conference September 18, 2021 carnitine is a precursor of the small molecule trimethyl amine-N-oxide (TMANO) which induces increased risk of cardiac disease. Our study utilizes targeted liquid chromatography mass spectrometry (LCMS/MS) analysis specifically to analyze changes in mice uninfected or infected with T. cruzi and treated with different concentrations of benznidazole, l-carnitine, or vehicle. Mice were infected and dosed 10 weeks post infection every day for 6 weeks and were euthanized 2 weeks post dosage. Blood serum was collected pre-treatment, post-treatment, and at endpoint. Based on targeted LCMS/MS analysis, TMANO production was not affected by l-carnitine treatment, indicating no increased risk of cardiac disease when compared to uninfected. Further analysis is being done focusing on protein markers of cardiac disease including collagen, fibronectin, and brain natriuretic peptide via RT-qPCR. This study thus far supports the use of l-carnitine in chronic CD. In addition, it provides insight to a novel CD treatment for future drug development. Key Words: T. cruzi, Chagas Disease, Targeted LCMS/MS, LCMS/MS, L-carnitine, Chronic Chagas Disease 12:15 PM - 1:15 PM Molecular Characterization Defines the Role of the Ig80 Subdomain for SMYD2-N2A Titin Binding (55) Mr. Adeleye Adewale, Graduate Research Assistant, Chemistry, Wayne State University SMYD2 is a protein methyltransferase whose role has been indicated in the organization of the muscle cell. SMYD2 associates with the giant muscle protein titin at one of its unique elements known as the N2A region. The N2A titin region has been recognized as a signaling hub in titin, and the binding of SMYD2 is indicated to protect this node from protease degradation, but SMYD2's mode of interaction is not well understood. We applied molecular cloning techniques, in making multiple subdomain constructs of the N2A region and studied their association with SMYD2 by bio-layer interferometry (BLI). Our analyses showed the Ig80 subdomain of N2A as the domain facilitating SMYD2’s binding to N2A. We also mapped the amino acid sequences in Ig80 allowing SMYD2‚Äôs binding to a PAVAP motif in proximity of its N-terminus. In addition, we observed that an additional motif in Ig80 interacts with SMYD2. Our subsequent analysis indicated a 13 sequence residue within Ig80 that may be exposed to interact with SMYD2 during unfolding of Ig80. Since Ig80’s unfolding may occur during muscle contraction and relaxation or pathologic conditions, our data may find a novel functional role of SMYD2 associated with an unfolded state of Ig80. Finally, we found that SMYD2 was able to bind and protect Ig80 that is susceptible to digestion by calpain-1. This indicates that Ig80 may be the segment of N2A predisposing its vulnerability to proteases. Putting together, our findings presents new understanding about SMYD2’s interaction in titin. Key Words: SMYD2; Titin; N2A Technical Sessions Biochemistry/Biophysics 3 2021 NOBCChE National Conference September 18, 2021 Impact of Multivalency and Encapsulation of Affinity Reagents and Catalysts (71) Brea Manuel, Chemistry, Emory University Increasing enzyme efficiency and protease resistance is highly desired for therapeutics such as enzyme replacement therapy (ERT) and for commercial uses such as pet waste degradation and removal. The most common method for increasing enzyme efficiency is mutating key residues in these enzymes. However, this is very time consuming, costly, and a matter of trial and error. In addition, many enzymes do not function properly when key residues are mutated. The most common method for bypassing protease degradation is pegylation. However, pegylation can also lead to an enzyme misfolding and functioning at a lower efficiency. Another method for bypassing protease degradation is encapsulating enzymes. We propose that by encapsulating an affinity reagent with an enzyme, we can sequester the enzyme substrate and place the substrate in close proximity to the enzyme via virus-like particle (VLP) encapsulation, leading to a higher
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