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dc.contributor.advisorConover, Gloria M
dc.creatorJacobs, Krystyna M
dc.date.accessioned2013-06-04T16:10:16Z
dc.date.available2013-06-04T16:10:16Z
dc.date.created2010-05
dc.date.issued2012-07-11
dc.date.submittedMay 2010
dc.identifier.urihttp://hdl.handle.net/1969.1/ETD-TAMU-2010-05-8115
dc.identifier.urihttp://hdl.handle.net/1969.1/148748
dc.description.abstractOur research focuses on the role of intermediate proteins in human disease. Desmin, a major intermediate filament protein in muscle cells, is organized into a central coiledcoil alpha helical domain flanked by globular head and tail domains. Our goal is to decipher the functional significance of the association of desmin to the giant thin filament protein nebulin at the sarcomeric Z-discs and its relation to muscle disease. Mutations in nebulin cause nemaline myopathy, a debilitating genetic muscle disease that affects children and adults alike. Previous research has shown that nebulin has a high affinity binding to desmin. However, little is known about the contribution of lower affinity binding desmin domains to nebulin or about the involvement of this interaction in nemaline myopathy. We hypothesize that the desmin 3-dimensional linkage to nebulin contributes to nemaline myopathy pathology. To test our hypothesis, we tested the binding profile of a nebulin-associated nemaline myopathy mutation to particular desmin domains using biochemical approaches. Our ELISA and GST-pull down assays showed that nebulin modules 160-164 bind to desmin?s central rod coil 2b and tail subdomains. Moreover, we found significantly decreased binding of the desmin coil 2b to the nemaline myopathy Nebulin M160-164 T5681P mutant as compared to nebulin M160-164. A 3-fold binding increase of the coil 2b was found in random alanine nebulin M160-164 L5646A mutant as compared to nebulin nemaline-associated nebulin M160-164 T5681P mutant, underscoring the importance of this region to the interaction of desmin and nebulin. Taken together, our findings suggest that differences in the binding profile of nemaline-associated nebulin mutations to desmin may contribute to our understanding the underlying molecular mechanism responsible for this disease. This knowledge may be significant because it may aid in devising new treatments for nemaline myopathy patients in the future.
dc.format.mimetypeapplication/pdf
dc.subjectNebulin
dc.subjectDesmin
dc.subjectNebulin M160-164
dc.subjectT5681P
dc.subjectL5646A
dc.subjectNemalin Myopathy mutations
dc.subjectintermediate filaments, sarcomere, striated muscle
dc.titleDeciphering the Effect of Nemaline-Myopathy Nebulin Mutations on Desmin Binding
dc.typeThesis
thesis.degree.departmentCollege of Veterinary Medicine and Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorHonors and Undergraduate Research
thesis.degree.nameBachelor of Science
dc.type.materialtext
dc.date.updated2013-06-04T16:10:16Z


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