Molecular Mechanism of ACAP1BAR-PH proteins assembling on membrane

Speaker: 
Jun Fan
Event Date and Time: 
Tue, 2016-11-01 11:00 - 12:30
Location: 
Hennings 318
Local Contact: 
Leanne Ebbs
Membrane deformation is a fundamental process that plays a significant role in cellular activities. BAR domain proteins are one of the best characterized protein families which bind to membrane and induce membrane deformation. Previously we reported a novel mechanism utilized by ACAP1 proteins, one member of BAR proteins, containing BAR-PH domain [Developmental Cell, 31:73, 2014]. This mechanism is different from conventional mechanisms where two BAR domains in each dimer (F-BAR, N-BAR) symmetrically bind to the negatively charged membrane through either strong electrostatic interactions or a hydrophobic loop insertion. In the case of the ACAP1 protein, the symmetric dimer binds to the membrane asymmetrically; the BAR domain does not directly bind to the membrane. Instead, the hydrophobic loop in only one of the PH domains of each protein inserts itself into the membrane, causing an imbalance of surface tension in two leaflets, thereby inducing membrane curvature. Several questions about this process remain: How do ACAP1 proteins form a protein lattice on the membrane? What key residues contribute to protein – protein interactions? What is the key intermediate structure during the assembly process? Why does the individual protein asymmetrically bind with the membrane? In this talk I will answer these questions, based on a comprehensive study combining molecular dynamics simulations, in vivo and in vitro mutation experiments, and electron microscopy. The results clearly demonstrate the protein assembly pathway, which is from a single protein dimer in the aqueous environment, to its asymmetrically binding to the membrane, and then to an intermediate structure (i.e., a protein tetramer in the same strand). The final stage is a protein lattice created via protein-protein interactions, mainly due to charged residues. According to our knowledge, this is the first time that the assembly pathway on a membrane of the BAR domain family is revealed based on strong experimental evidence. We believe it will bring new insights and significant impact to the membrane deformation process.
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