Galectin‐1 (Gal‐1), a protein that impacts the fate and function of immune cells known to fight infection, eliminates cancer, and promotes inflammation, is found in most mammalian tissues at low levels. A small 130 amino acid “jelly‐roll” shaped ß‐galactoside‐binding lectin with a hydrophobic core, Gal‐1 plays a role in controlling intracellular processes, such as cell cycle progression and cell proliferation. Gal‐1 binds with high affinity to glycoconjugates galactose (Gal) and N‐acetylglucosamine (GlcNAc) by van der Waals forces and hydrogen bonding via a highly conserved carbohydrate recognition domain. Because native Gal‐1 oxidizes rapidly and loses its carbohydrate‐binding activity, studying the effect of Gal‐1 has been difficult. The Dimitroff laboratory engineered a Gal‐1 – human immunoglobulin Fc chimeric molecule (Gal‐1hFc), which facilitates dimerization while preventing oxidation‐induced multimerization. Experimental evidence has demonstrated that Gal‐1hFc behaves like native Gal‐1, enabling the use of the chimera to study Gal‐1’s effect on immune responses. The Governor’s Academy SMART (Students Modeling A Research Topic) Team designed a model using 3D printing technology to provide further evidence of Gal‐1hFc’s structure and binding function. Grant Funding Source: Supported by grants from NIH‐CTSA UL1RR031973 and NIH/NCI RO1CA118124
Helicases are highly conserved enzymes that unwind the double helix of DNA, providing access to single‐stranded DNA. Found in all living organisms and viruses, helicases function as motor proteins in replication, transcription, and remodeling of DNA. A common sexually‐transmitted oncovirus, human papillomavirus (HPV) uses E1 helicase, the most studied helicase protein because of the ease by which it can be isolated. The only enzyme encoded in the HPV episome, E1 hexameric helicase is a ring‐shaped translocase that belongs to the AAA+ family and superfamily 3. E1 has near exact rotational symmetry with respect to its six subunits. Each monomer comprises a central five‐stranded anti‐parallel beta‐sheet and six alpha helices. Conserved sequence motifs Walker A and B and an arginine finger participate in the binding and hydrolysis of ATP causing conformational changes in β‐hairpins, powering the walking movement along the ssDNA. Assembling first as a double‐trimer at the replication origin and then into two homohexamers on opposing strands, E1 separates the dsDNA into ssDNA by occlusion in the 3'→5' direction. Asymmetric sequential progression of ATP hydrolysis around the hexameric ring at catalytic sites between monomers powers translocation of E1. An understanding of its functional domains and how they interact with each other, DNA, and host proteins is necessary to elucidate the overall mechanism of helicase function. Using 3D printing technology, The Governor's Academy SMART (Students Modeling A Research Topic) Team modeled the E1 helicase to provide vital insight into the mechanism of eukaryotic DNA replication and potentially promote development of therapeutic treatments.
Amyloidosis, a disease caused by aggregation of misfolded protein, affects millions of people. Deposition of aggregates interferes with normal function of organs and is sometimes caused by mutant forms of transthyretin (TTR), a protein found in blood and cerebrospinal fluid. Wild‐type TTR is a homotetramer that carries thyroxine (T4), a hormone that regulates metabolism. The tetramer arrangement forms a central channel which contains binding sites for T4. One point mutation responsible for V122I is amyloidogenic and common in African Americans (4% allele frequency). This substitution likely causes destabilization of TTR's native conformation, promoting dissociation to partially unfolded monomers. The monomers aggregate to form insoluble amyloid fibrils that are deposited in the heart. Valine and isoleucine, both hydrophobic amino acids, differ only by one methyl group; how this small alteration causes cardiac amyloidosis is unclear. T4 analog diflunisal, previously used to treat the disease, inhibits the vital enzyme cyclooxygenase. The Governor's Academy SMART (Students Modeling a Research Topic) team designed a model using 3D printing technology to highlight important structural features of TTR. A thorough understanding of the T4 binding site within TTR will allow design of effective kinetic stabilizers. Supported by a grant from NIH‐SEPA.
AIDS is a major worldwide epidemic caused by human immunodeficiency virus (HIV). In 2007, there were 33 million people living with HIV/AIDS. A protein in the HIV envelope, gp120 recognizes CD4, a protein found on the surface of human T cells. Binding of gp120 to CD4 enables HIV to attach and gain access to the cell. Neutralizing antibodies with broad reactivity to HIV have been identified. One such antibody, IgG1 b12, binds the CD4‐binding site of gp120, blocking CD4 attachment. Antibody b12 comprises two identical heavy chains and two identical light chains held together by disulfide bonds, forming a Y. The chains have constant and variable regions. The tip of each arm contains an antigen binding site (Fab), allowing the antibody to bind specifically to a particular antigen. The base of the antibody (Fc region) is made up of two heavy chains. Flexible hinges connect Fab arms to the Fc allowing conformation changes. A finger‐like projection extending above the surface of the antigen binding site allows it to fit into the recessed binding site of gp120. The Governor's Academy SMART (Students Modeling a Research Topic) team, in collaboration with MSOE, designed a model using 3D printing technology to highlight the structural features of b12. Understanding its structure and the nature of its interaction with gp120 may allow development of an effective vaccine against HIV‐1. Supported by a grant from theNIH‐NCRR‐SEPA
Members of the ADAMs (A Disintegrin And Metalloprotease) family are involved in cell migration, invasion and growth factor signaling, all key processes in cancer. Pancreatic ductal adenocarcinoma (PDAC), marked by massive infiltration of tumor cells into the pancreas and metastasis into liver and lungs, has the highest mortality rate of all solid organ cancers. In PDAC, high ADAM8 levels correlate with decreased survival. In cell membranes, ADAM8 associates with itself to allow autocatalytic activation. ADAM8 then binds to β1‐integrin, a transmembrane receptor that attaches cells to the extracellular matrix (ECM) and allows communication across the membrane. Both interactions cause ECM remodeling via intracellular signaling pathways by phosphorylation of β1‐associated kinases focal adhesion kinase and extracellular signal‐regulated kinase which in turn activate the release of matrix‐metalloproteinases, potent mediators of ECM degradation. The Governor's Academy SMART (Students Modeling A Research Topic) team designed a model using 3D printing technology to highlight structural features, providing functional insight into the mechanism by which ADAM8 causes tumor progression in PDAC. Since its protein‐protein interactions are crucial for its function in tumors, blocking ADAM8 to limit invasive tumor growth is a promising therapeutic strategy. Supported by a grant from NIH‐SEPA 1R25OD010505–01
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