Structural characterization of interaction of K11 and K63 mixed-linkage polyubiquitin chains with the tUIMs of epsin1

Ubiquitylation or covalent attachment of ubiquitin (Ub) to a variety of substrate proteins in cells is a versatile post-translational modification involved in the regulation of numerous cellular processes. The distinct messages that polyubiquitylation encodes are attributed to the multitude of conformations possible through attachment of ubiquitin monomers within a polyubiquitin chain via a specific lysine residue. Thus the hypothesis is that linkage defines polyubiquitin conformation which in turn determines specific recognition by cellular receptors. Ubiquitylation of membrane surface receptor proteins plays a very important role in regulating receptor-mediated endocytosis as well as endosomal sorting for lysosomal degradation. Epsin1 is an endocytic adaptor protein with three tandem UIMs (Ubiquitin Interacting Motifs) which are responsible for the highly specific interaction between epsin and ubiquitylated receptors. Epsin1 is also an oncogenic protein and its expression is upregulated in some types of cancer. Recently it has been shown that novel K11 and K63 mixed-linkage polyubiquitin chains serve as internalization signal for MHC I (Major Histocompatibility Complex I) molecule through their association with the tUIMs of epsin1. However the molecular mode of action and structural details of the interaction between polyubiquitin chains on receptors and tUIMs of epsin1 is yet to be determined. This information is crucial for the development of anticancer therapeutics targeting epsin1. The molecular basis for the linkage-specific recognition of K11 and K63 mixed-linkage polyubiquitin chains by the tandem UIMs of the endocytic adaptor protein epsin1 is investigated using a combination of NMR methods.

TRADITION AND INNOVATION: ANALYSIS AND PERFORMANCE OF SELECTED COMPOSITIONS FOR VIOLONCELLO BY HEITOR VILLA-LOBOS

Brazilian composer Heitor Villa-Lobos (1887-1959) began his musical career as a cellist. When he was only twelve years old, it became imperativeupon the sudden and untimely death of his fatherthat the young Villa-Lobos earn money as a cellist to provide financial support for his mother and sisters. Villa-Lobos's intimate relationship with the cello eventually inspired him to compose great music for this instrument. This dissertation explores both the diversity of compositional technique and the evolution of style found in the music for cello written by Villa-Lobos. The project consists of two recorded recital performances and a written document exploring and analyzing those pieces. In the study of the music of Villa-Lobos, it is of great interest to consider the music's traditional European elements in combination (or even juxtaposition) with its imaginative and sometimes wildly innovative Brazilian character. His early works were greatly influenced by European Romantic composers such as Robert Schumann, Frédéric Chopin, and the virtuoso cellist/composer David Popper (whom Villa-Lobos idolized). Later, Villa-Lobos flourished in a newfound compositional independence and moved away from Euro-romanticism and toward the folk music of his Brazilian homeland. It is intriguing to experience this transition through an exploration of his cello compositions. The works examined and performed in this dissertation project are chosen from among the extensive number of Villa-Lobos's cello compositions and are his most important works for cello with piano, cello with another instrument, and cello with orchestra. The chosen works demonstrate the evolving range and combination of characteristic elements found in Villa-Lobos's compositional repertoire.