Theoretical studies of Membrane Proteins : Properties, Prediction Methods and Genome-wide analysis

Membrane proteins are a large and important class of proteins. They are responsible for several of the key functions in a living cell, e.g. transport of nutrients and ions, cell-cell signaling, and cell-cell adhesion. Despite their importance it has not been possible to study their structure and organization in much detail because of the difficulty to obtain 3D structures. In this thesis theoretical studies of membrane protein sequences and structures have been carried out by analyzing existing experimental data. The data comes from several sources including sequence databases, genome sequencing projects, and 3D structures. Prediction of the membrane spanning regions by hydrophobicity analysis is a key technique used in several of the studies. A novel method for this is also presented and compared to other methods. The primary questions addressed in the thesis are: What properties are common to all membrane proteins? What is the overall architecture of a membrane protein? What properties govern the integration into the membrane? How many membrane proteins are there and how are they distributed in different organisms? Several of the findings have now been backed up by experiments. An analysis of the large family of G-protein coupled receptors pinpoints differences in length and amino acid composition of loops between proteins with and without a signal peptide and also differences between extra- and intracellular loops. Known 3D structures of membrane proteins have been studied in terms of hydrophobicity, distribution of secondary structure and amino acid types, position specific residue variability, and differences between loops and membrane spanning regions. An analysis of several fully and partially sequenced genomes from eukaryotes, prokaryotes, and archaea has been carried out. Several differences in the membrane protein content between organisms were found, the most important being the total number of membrane proteins and the distribution of membrane proteins with a given number of transmembrane segments. Of the properties that were found to be similar in all organisms, the most obvious is the bias in the distribution of positive charges between the extra- and intracellular loops. Finally, an analysis of homologues to membrane proteins with known topology uncovered two related, multi-spanning proteins with opposite predicted orientations. The predicted topologies were verified experimentally, providing a first example of "divergent topology evolution".

France, Germany and the United Kingdom Cooperation in Times of Turbulence

This thesis deals with cooperation between France, Germany and the United Kingdom within the area of foreign and security policy. Two case studies are presented, one of them concerning cooperation between the three states within and outside institutions in 1980 following the Soviet invasion of Afghanistan, and the other dealing with cooperation concerning the crisis in Macedonia in 2001. In accordance with the approach of neoliberal institutionalism the primary hypothesis is that cooperation is primarily determined by the interests of states but it is also limited by norms and affected by the institutions of which the three states are members. The study describes the large variety of forms of cooperation that exist between France, Germany and the United Kingdom, in which the United States also plays an important part, and which also includes their cooperation within a number of international institutions. The study also points to the new forms of interaction between states and institutions that have come about since the Cold War ended, and which give a stronger role to institutions and the cooperation between them. Still, however, states retain a decisive role in cooperation within the field of foreign and security policy.