All cells possess hydrophobic plasma membranes which separate the cellular cytosol from the external environment. Anchored within the membrane are specialized proteins which perform a multitude of important tasks. As these membrane proteins have evolved to reside and function within the hydrophobic cellular membrane, the cell must complete the challenging task of trafficking them from the aqueous cytosol and inserting them into the membrane. If membrane proteins are mis-inserted, they may aggregate and become toxic to the cell. The difficulty of this problem is magnified in eukaryotes, which possess additional internal membranes as part of their endomembrane organellar system. The process by which membrane proteins are synthesized and inserted into the membrane is termed membrane protein biogenesis. Many proteins in eukaryotes are inserted co-translationally, or as they are synthesized, by the protein-conducting channel of the endoplasmic reticulum. However, it is becoming more and more evident that previously unappreciated factors play important roles in membrane protein trafficking, insertion, and quality control. Here, I present research elucidating the structure and function of a number of membrane protein biogenesis factors found in eukaryotes. Specifically, I present evidence that the poorly studied protein TMCO1 possesses functional and structural features similar to those of the better characterized membrane protein insertases it is evolutionarily related to. Additionally, we see that TMCO1 associates with NOMO, Nicalin, CCDC47, and TMEM147; pointing to a role in membrane protein biogenesis for these uncharacterized proteins. Finally, we show that Msp1, a mitochondrial protein, is a functional hexamer capable of directly extracting mislocalized tail anchored membrane proteins from the mitochondrial outer membrane; providing further evidence for its function in membrane protein quality control.




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