Influenza is a rapidly mutating RNA virus causing mortality and morbidity in humans.The three different strains of influenza are characterized by different surface glycoproteins. Hemagglutinin (HA) is one of the primary binding proteins of Influenza A, the most prevalent strain of the virus. HA is a trimer, with each macromolecule consisting of a head and stalk region. The head region recognizes sialic acid on the host cell surface, initiating viral infection. The sialic acid binding site is highly susceptible to antigenic drift, and is the primary target of current vaccine development. The binding site consists of a loop‐helix‐loop region that allows for the attachment between HA and sialic acid. Because this region is both constantly mutating and strain specific, new vaccines need to be developed annually. Most antigenic drift is located within two antigenic sites. The Marshfield High School SMART (Students Modeling A Research Topic) Team will be modeling the sialic acid binding site on HA to demonstrate how the protein triggers viral infection. The stalk domain functions to mediate fusion of the viral and endosomal membranes. During this process, the domain undergoes extensive structural rearrangement. As such, the stalk domain is a more suitable vaccine target because it is conserved across strains and is not as susceptible to genetic drift. Therefore, emerging research has focused on the stalk region for more promising vaccinations, and maybe an eventual elimination of the need to develop a new vaccine every year. The Marshfield Research Foundation is currently studying influenza vaccine effectiveness and safety including the effects of repeated vaccination on immunity.
Human Papilloma Virus (HPV) is the most common sexually transmitted pathogen in humans and the primary cause of cervical cancer. The tumor suppressor p53, in its normal state, regulates cell growth and survival through mechanisms including DNA repair and apoptosis. When p53 binds to the HPV E6 oncoprotein, a binding pocket is formed, causing partial inactivation of the tumor suppressor. E6 is found in the L1 capsid protein of HPV, and directly causes the degradation of p53, as well as the activation of telomerase[, a ribonucleic enzyme that prevents the decline in chromosome function, and therefore allows HPV infected cells proliferate leading to the development of cancer. Researchers are attempting to identify potential binding pockets in E6 in hopes of forming a protein inhibition mechanism that can block further proliferation of cervical cancer. Understanding the regulation of E6 in human papillomavirus will allow the formation of vaccinations of higher specificity as well as treatments for cervical cancer. The Marshfield High School MSOE Center for BioMolecular Modelling for SMART Team used 3D Modelling and printing technology to examine structure‐ function relationships of the E6 oncoprotein and p53 tumor suppressor.
When the contents of the bloodstream are filtered by the kidney, glucose is reabsorbed. Familial glycosuria, a benign disorder often attributed to genetic variants in the gene SLC5A2 which encodes the protein Sodium Glucose Transporter 2 (SGLT2), prevents reabsorption of glucose leading to an excess amount in urine. SGLT2 is used for glucose reabsorption, and when functioning properly, about 90% of glucose from the urine is reabsorbed into the bloodstream. Upon glucose and sodium binding, SGLT2 undergoes a conformational change, where the structure shifts from an outward to an inward facing orientation, allowing glucose to be released. Recently, two novel variants in SLC5A2 have been identified in the Marshfield Clinic patient population; further research is being conducted to determine whether these variants impact glucose transportation and how they affect physiological output. To research this, homology models of WT SGLT2 were constructed and analyzed based on a previously solved structure of a bacterial SGLT protein (vSGLT). It can be concluded that SGLT2's structure is composed of 14 transmembrane helices which surround both galactose/glucose and sodium binding sites. Recently, SGLT2 has become a popular target for Type II diabetes therapeutics. These drugs inhibit SGLT2, as they prevent glucose to be reabsorbed; thus, glucose is excreted out of the body. Further understanding how genetic variants effect SGLT2 structure and function may allow practitioners to properly prescribe medications and prevent adverse drug reactions when treating patients with Type II diabetes.Support or Funding InformationMarshfield Clinic Research FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glaucoma, the leading cause of vision loss worldwide, occurs when elevated intraocular pressure damages the optic nerve. Intraocular pressure increases when there is a blockage of the trabecular meshwork, a drainage system at the base of the cornea. This process is dictated by a bidirectional signalling protein composed of a specific combination non‐covalently bonded α and β integrin subunits called the αvβ3 integrin. In an inactive state, the integrin is is positioned as a switchblade and its cytoplasmic tails are held together by a salt bridge. To become activated, the integrin must extend; the salt bridge must be broken, and the cytoplasmic tails spread apart. During outside‐in signalling, a ligand binds to the αvβ3 integrin which forces it to re‐conform to the active state and results in the transmission of mechanical and chemical cues from the extracellular matrix into the cell by means of a protein cascade. This leads to the trabecular meshwork becoming more dense and interwoven. A possible hypothesis to explain the connection between integrins and glaucoma is that the trabecular meshwork can not turn off the αvβ3 integrin which results in a reduced outflow of the aqueous humor and thus, increased intraocular pressure. Understanding the modulation of intraocular pressure by integrins can lead to therapeutic targets to treat glaucoma. The Marshfield High School MSOE Center for BioMolecular Modelling for SMART Team used 3D Modelling and printing technology to examine structure‐ function relationships of the αvβ3 integrin protein.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Human Papillomavirus (HPV) is the most common sexually transmitted pathogen in humans and the primary cause of cervical cancer. The tumor suppressor p53, in its normal state, regulates cell growth and survival through mechanisms including DNA repair and apoptosis. The E6 oncoprotein directly inhibits p53s function by attaching itself to a ubiquitin ligase, E6AP, which in turn forms a complex with p53. E6 and E6AP form a heterodimer by binding at a leucine‐rich docking site, known as the LxxLL motif. The heterodimer then forms a binding pocket with p53, which is the cause of the inactivation of p53 function. Researchers are attempting to identify potential binding pocket function in the complex in order to form a protein inhibition mechanism that can block further proliferation of cervical cancer. Understanding the interactions of the E6/E6AP/p53 complex is leading to the development of unique antiviral and chemotherapeutic agents for cervical cancer. The Marshfield High School MSOE Center for BioMolecular Modellng for SMART Team used 3D modelling and printing technology to examine the structure‐function relationships of the E6/E6AP/p53 complex. Support or Funding Information Marshfield Clinic LaboratoriesMSOE Center for BioMolecular ModelingMarshfield Area Community Foundation
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