The extracellular domain of the LDL receptor was my top hit and showed evidence of a mutation but was not the same as before

The extracellular domain of the LDL receptor was my top hit and showed evidence of a mutation but was not the same as before. Aspartic acid is still replaced by glycine; however, the mutation has occurred on a different amino acid. Previously, the mutation was on amino acid 221 but here it is on amino acid 200 as seen in figure 7. The top hit was a large structure however, it’s easier to work with smaller fragments of the protein so we used the 1AJJ hit. The 1AJJ hit is an LDL receptor ligand binding molecule 5 and represents the specific location of the mutation of the LDL receptor, which is the change of an aspartic acid to glycine on amino acid 26 shown in figure 8. The 1AJJ original paper title is “Protein folding and calcium binding defects arising from familial hypercholesterolemia mutations of the LDL receptor” and the authors are Blacklow, S.C. and Kim, P.S. From the structure produced, the normal wild type structure forms polar contacts between the calcium ion and the protein, whereas the mutant residue would be unable to do this. From the structure produced using PyMol the 1AJJ has a Ca2+ cage that is used to stabilizes the LDLR by forming polar contacts. LDLR is a cell surface receptor that transports LDL into cells via mediated endocytosis. Patient’s suffering from Familial Hypercholesterolemia as our patient is, there are point mutations in the LDLR which I distinguished earlier as an A to G mutation. So, I can presume that by glycine being present, polar contacts are not formed resulting in the receptor to destabilize. LDLR cannot remove the LDL from the blood, resulting in the accumulation of blood cholesterol in the body, leading to patients’ symptoms such as cutaneous xanthomas and narrowing of the aorta.

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