Membrane-protein insertion: One helix and one amino acid at a time

Membrane proteins are critical components of all cells, controlling, e.g., signaling, nutrient exchange, and energy production, and are the target of over half of all drugs currently in production.  At an early stage of their synthesis, nearly all membrane proteins are directed to a protein-conducting channel, the SecY/Sec61 complex, which permits access to the membrane via its lateral gate.  By combining molecular dynamics simulations with cryo-electron microscopy data, we recently resolved the first structure of a membrane-protein-insertion intermediate state of SecY bound to a translating ribosome, with a transmembrane (TM) segment...

Membrane proteins are critical components of all cells, controlling, e.g., signaling, nutrient exchange, and energy production, and are the target of over half of all drugs currently in production.  At an early stage of their synthesis, nearly all membrane proteins are directed to a protein-conducting channel, the SecY/Sec61 complex, which permits access to the membrane via its lateral gate.  By combining molecular dynamics simulations with cryo-electron microscopy data, we recently resolved the first structure of a membrane-protein-insertion intermediate state of SecY bound to a translating ribosome, with a transmembrane (TM) segment caught at the open gate. Beginning from that state, multi-microsecond simulations of different putative TM segments at the gate have been carried out. The simulations reveal spontaneous motion of the TM segment, either inserting into the membrane or toward the channel interior, depending on its sequence, in agreement with a thermodynamic partitioning proposed previously.  However, attempts to quantify this partitioning led to experiment- and simulation-based scales for the free-energy insertion cost of various amino acids that differ significantly, leaving open the question of the true insertion process.  Now, using novel free-energy calculations and by carefully matching the context of the simulations to experiment, I will demonstrate a significantly improved agreement for multiple membrane-protein-insertion assays.  Thus, it is suggested that the discrimination step between membrane-inserted and secreted states of a nascent protein occurs primarily in the SecY channel.

Event Details

Date/Time:

  • Date: 
    Friday, March 9, 2012 - 10:00am

Location:
ES&T Room L1255