When functioning properly, the immune system protects the body from foreign invaders with the help of T‐cells. An error in the formation of T‐cells in the thymus can lead to autoimmune diseases in which the T‐cells attack normal body tissues. When a T‐cell binds to an antigen, a signal transduction pathway is activated, forming a multimeric signaling complex known as the TCR signalosome. LCK, part of the signalosome, is a lymphocyte‐specific protein tyrosine kinase that phosphorylates a variety of proteins in order to activate the T‐cell receptor pathway. TCR stimulation also leads to the activation of LYP, a lymphoid tyrosine phosphatase that down regulates TCR signaling by removing phosphates from the signaling intermediates of the TCR signalosome. LYP also dephosphorylates Y394 of LCK, thus inactivating the kinase and inhibiting TCR signaling. The LYP R620W mutation prevents LYP from binding to the signalosome, resulting in a gain‐of‐function, leading to increased inhibition of TCR signaling. The LYP R620W mutation has been linked to a wide spectrum of human diseases, including a decreased risk in Crohn’s disease and increased risk to rheumatoid arthritis, and possible links to non‐autoimmune disorders such as cardiovascular disease. The Marshfield SMART (Students Modeling A Research Topic) Team modeled the mutated protein LYP R620W using 3D technology. Grant Funding Source: Supported by grants from NIH‐CTSA and NIH‐SEPA.
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.
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