막 단백질 구조의 진화 및 기능 다양성 연구

Abstract

Membrane proteins play important roles in the biology of the cell. Membrane proteins are located on the cell surface to mediate cell-cell communication by identifying and attaching to other cells and transmit interior/exterior signals through the membrane bilayers. Due to their biological functions, many membrane proteins are primary drug target, and also must be essential player in developing the multicellularity needed for metazoan evolution. However, experimental difficulties and lack of structural information have limited the functional characterization of membrane proteins, because the membrane environment impose particular constrains onto the structure and evolution of transmembrane (TM) proteins that are not present for soluble proteins.First, I elucidated the structural and functional relationship between membrane and soluble proteins to understanding function of membrane proteins based on large-scale structure comparisons. Of the membrane proteins of known structure, we found that a remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure. Moreover, 41% of known water soluble protein structures share a domain with an already known membrane protein structure. We also found that functional residues are frequently conserved between extramembrane domains of membrane and soluble proteins that share structural similarity. These results suggest membrane and soluble proteins readily exchange domains and their attendant functionalities. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. The high level of structural overlap between the two classes of proteins provides an opportunity to employ the extensive information on soluble proteins to illuminate membrane protein structure and function, for which much less is known. To this end, we employed structure guided sequence alignment to elucidate the functions of membrane proteins in the human genome. Our results bridge the gap of fold space between membrane and water soluble proteins and provide a resource for the prediction of membrane protein function. A database of predicted structural and functional relationships for proteins in the human genome is provided at sbi.postech.ac.kr/emdmp.Second, I investigated how rampant domain exchange between membrane and soluble proteins contribute to the evolution of multicellular organisms. A central question in animal evolution is how multicellular animals evolved from unicellular ancestors. I hypothesized that membrane proteins must be key players in the development of multicellularity because they are well positioned to form the cell-cell contacts and to provide the intercellular communication required for the creation of complex organisms. Here I found that a major mechanism for the necessary increase in membrane protein complexity in the transition from protozoan to metazoan life was the new incorporation of domains from soluble proteins. The membrane proteins that have incorporated soluble domains in metazoans are enriched in many of the functions unique to multicellular organisms such as cell-cell adhesion, signaling, immune defense and developmental processes. They also show enhanced protein-protein interaction (PPI) network complexity and centrality, suggesting an important role in the cellular diversification found in complex organisms. These results expose an evolutionary mechanism that contributed to the development of higher life forms.