Cotranslational folding of integral membrane proteins

The great majority of integral membrane proteins are cotranslationally inserted in the inner bacterial membrane or the eukaryotic endoplasmic reticulum membrane with the aid of the SecYEG translocon in bacteria or the homologous Sec61 translocon in eukaryotes.

Despite much progress in the past two decades, we are still ignorant of the dynamic aspects of membrane protein biogenesis: when during translation does a TMH begin to insert into the membrane and when is its insertion finished, how does insertion depend on the detailed amino acid sequence, how do charged residues affect insertion when they begin sensing the membrane potential, can membrane proteins start to fold already during translation (as soluble proteins can), and can events at the level of the translocon be communicated back to the peptidyl transferase center in the ribosome to affect, e.g., the translation rate?The current proposal is focused on using our newly developed Force Profile Analysis method and cryo-EM to analyze the cotranslational insertion and folding of a range of natural and designed inner membrane proteins, in order to improve our understanding of the dynamics of these processes.

Progress in this area will add important pieces to our knowledge of membrane protein biogenesis, and may be significant to improve methods for overexpression of membrane proteins and to better understand diseases related to membrane protein misfolding.