A Systematic Analysis of Intertwined Homomeric Proteins

Intertwined homomers are multimeric protein complexes, whereby identical subunits appear to exchange small segments or compact protein substructures (domains). Using a formal definition of intertwined homo-oligomers, we survey the Protein Data Bank for all such complexes. Results show that intertwining occurs in 13,442 (24%) of all surveyed structures. This thesis charts the landscape of intertwined proteins by examining their structural properties and classifying them accordingly. We define three primary categories to classify intertwined proteins, based on the structural nature of the exchanged element. S-type intertwined proteins exchange one contiguous chain segment and account for the majority of all intertwined homomers (72%). D-type intertwined proteins (10%) exchange structural domains. M-type intertwined proteins (18%) display complex swapping topologies that exchange multiple segments or domains. The studies presented in this thesis provide unique insights into the role of intertwining in homomeric association. For instance, intertwining promotes homomer formation for all three classes of intertwined proteins, particularly among the S-type class and smaller protein structures. Additionally, we found that intertwining provides some homomeric proteins with the ability to adopt different inter-subunit geometries, with minimal changes in the subunit-subunit interface. These changes in inter-subunit geometry were thoroughly investigated among D-type intertwined homomers and were found to be associated with a number of roles, such as DNA binding and functional regulation.Ph.D