HEXA+Protein+Interactions

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The key to understanding any biological system is understanding the relationships and interactions involved in the system. The key to understanding disease is understanding the interactions involved in both diseased individuals and healthy individuals. Although the root cause of genetic diseases are usually some sort of genetic mutation(s), a problem in the inheritable "blueprint" of an organisms, the disease manifests in the product of the mutated gene or genes -- proteins. If an organism's genome can be described as a blueprint, directions for constructing a machine that is an organism, proteins are the parts that make up the machine, and that function together to make the machine work. Although the genome contains all the information to produce an organism, individual genes provide information for making the individual parts, or proteins. =====

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But if you were to take a machine, like a car, for example, you could break it down in to functioning systems, like the engine, the transmission, the drivetrain, and the stereo. Within each of these systems, their are individual parts, that, by themselves, are really incapable of doing anything. But, when all of these parts interact with each other, they produce a system capable of activities that contribute to the overall functioning of the car. Now, although we often take for granted the impact and importance of a tiny little spark plug, and its seemingly inconsequential existence, when one tiny spark plug is not firing, our car may not work. Genetic diseases are similar to this example in the sense that they can cause individual proteins, the tiny parts that interact with one another in our body's systems, to lose their function, sometimes causing catastrophic failure in our bodies. =====

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TSD is caused by a genetic mutation that results is a non-functioning hexosaminidase A enzyme protein. But to understand why this protein is important and why its loss of function leads to such a terrible disease, it is important to understand the "system" that it is apart of and the interactions it has with other proteins in healthy individuals. The above image, obtained from STRING 9.1, a database of known and predicted protein to protein interactions, shows the relationship and interactions of the gene products associated with the HEXA gene product, the alpha subunit of the hexosaminidase A enzyme. =====


 * = ==__Polypeptide__== ||= ==__Function (Known or Predicted)__== ||
 * = HEXA (Hexosaminidase A alpha subunit) || Responsible for the degradation of GM2 gangliosides, and a variety of other molecules containing terminal N-acetyl hexosamines, in the brain and other tissues. ||
 * HEXB (Hexosaminidase A beta subunit) || Responsible for the degradation of a variety of molecules containing terminal N-acetyl hexosamines, in the brain and other tissues. Also provides binding site for GM2A. ||
 * GM2A (GM2 ganglioside activator) || Binds gangliosides and stimulates ganglioside GM2 degradation. It stimulates only the breakdown of ganglioside GM2 and glycolipid GA2 by beta-hexosaminidase A. It extracts single GM2 molecules from membranes and presents them in soluble form to beta-hexosaminidase A for cleavage of N-acetyl-D-galactosamine and conversion to GM3. ||
 * GUSB (glucuronidase, beta) || Plays an important role in the degradation of dermatan and keratan sulfates. ||
 * GLB1 (galactosidase, beta 1) || Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans. ||
 * NAGK (N-acetylgalactosaminidase, alpha) || Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids ||
 * IDUA (iduronidase, alpha-L) || Catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate. ||
 * NAGA (N-acetylglucosamine kinase) || Converts endogenous N-acetylglucosamine (GlcNAc), a major component of complex carbohydrates, from lysosomal degradation or nutritional sources into GlcNAc 6-phosphate. Also has ManNAc kinase activity (By similarity). ||
 * <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">GLA (galactosidase, alpha) || <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">Hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. ||
 * <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">IDS (iduronate 2-sulfatase) || <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">Required for the lysosomal degradation of heparan sulfate and dermatan sulfate ||
 * <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">CHIT1 (chitinase 1/chitotriosidase) || <span style="font-family: 'Trebuchet MS',Helvetica,sans-serif;">Degrades chitin and chitotriose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity ||

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The above table provides information on the individual proteins in the image. The image also contains several colored lines. The above image is an "evidence view" of the protein to protein relationships. What this means is that the colored lines do not have anything to do with the relationships or interactions between the proteins, but the evidence supporting their interactions. The more lines between two peptides, the more evidence to support their relationship. As can be seen in the evidence view (above), the most evidence has established the relationship and interactions between HEXA, HEXB, and the GM2A activator. STRING 9.1 also supplies a more interesting "actions view" (below). =====



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This image provides a much more telling relationship. The blue colored lines represent a physical binding relationship between the peptides, showing that HEXA, HEXB, and GM2A all bind to each other. The purple lines represent a catalytic and/or activating relationship between peptides, with the round node indicating which peptide is the catalyst/activator. The above image shows that GM2A has activating effects on the two subunits of the hexosaminidase A enzyme. =====

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These images help us to visualize the relationships of these peptide sequences, diagraming how GM2 ganglioside degradation is achieved, and showing how a loss of function in any of the three critical components of this system will result in gangliosidosis. =====

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