Proapoptotic BAX protein is largely cytosolic in healthy cells, but it oligomerizes and translocates to mitochondria upon receiving apoptotic stimuli. A long-standing challenge has been the inability to capture any structural information beyond the onset of activation. Here, we present solution structures of an activated BAX oligomer by means of spectroscopic and scattering methods, providing details about the monomer-monomer interfaces in the oligomer and how the oligomer is assembled from homodimers. We show that this soluble oligomer undergoes a direct conversion into membrane-inserted oligomer, which has the ability of inducing apoptosis and structurally resembles a membrane-embedded oligomer formed from BAX monomers in lipid environment. Structural differences between the soluble and the membrane-inserted oligomers are manifested in the C-terminal helices. Our data suggest an alternative pathway of apoptosis in which BAX oligomer formation occurs prior to membrane insertion.
a b s t r a c tIn the past, the utilization of the limb prosthesis has improved the daily life of amputees or patients with movement disorders. However, a leg-amputee has to take a series of training after wearing a limb prosthesis, and the training results determine whether a patient can use the limb prosthesis correctly in her/his daily life. Limb prosthesis vendors thus desire to offer the leg-amputee a complete and wellorganized training process, but they often fail to do so owing to the factors such as the limited support of human resource and financial condition of the amputee. This work proposes a prosthesis training system that the amputees can borrow or buy from the limb prosthesis vendors and train themselves at home. Instant feedback messages provided by the prosthesis training system are used to correct their walking postures during the self-training process. An embedded chip is used as a core to establish a body area sensor network for the prosthesis training system. RFID readers and tags are employed to acquire the 3D positioning information of the amputee's limbs in this work to assist in diagnosing the amputee's walking problem. A series of simulations were conducted and the simulation results exhibit the effectiveness and practicability of the proposed prosthesis training system.
Apoptotic BAX protein functions as a critical gateway to mitochondria-mediated apoptosis. A diversity of stimuli has been implicated in initiating BAX activation, but the triggering mechanism remains elusive. Here we study the interaction of BAX with an intrinsically disordered BH3 motif of Bim protein (BimBH3) using ESR techniques. Upon incubation with BAX, BimBH3 binds to BAX at helices 1/6 trigger site to initiate conformational changes of BAX, which in turn promotes the formation of BAX oligomers. The study strategy is twofold: while BAX oligomerization was monitored through spectral changes of spin-labeled BAX, the binding kinetics was studied by observing time-dependent changes of spin-labeled BimBH3. Meanwhile, conformational transition between the unstructured and structured BimBH3 was measured. We show that helical propensity of the BimBH3 is increased upon binding to BAX but is then reduced after being released from the activated BAX; the release is due to the BimBH3-induced conformational change of BAX that is a prerequisite for the oligomer assembling. Intermediate states are identified, offering a key snapshot of the coupled folding and binding process. Our results provide a quantitative mechanistic description of the BAX activation and reveal new insights into the mechanism underlying the interactions between BAX and BH3-mimetic peptide.
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