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    • Unlike the bacterial SRP pathway for which the energetics

    2022-08-09

    Unlike the bacterial SRP pathway for which the energetics, kinetics, and structure of almost every intermediate have been characterized, multiple questions remain for the GET pathway (Figure 3, marked with ‘?’). First, the targeting pathway demands distinct activities of Get3 before and after substrate loading: prior to TA binding, Get3 must be ATP bound and tightly bound to Get4/5; after TA loading, Get3 must hydrolyze ATP and detach from Get4/5 so that it can instead interact with the Get1/2 receptor at the ER. Although a structure of Get3–TA peptide complex is now available, the conformation of Get3 in this structure is similar to that in the Get3–Get4/5 complex; it is unclear how the TA substrate drives the transition of Get3 from Get4/5 to the Get1/2 receptors. In addition, the structures of important intermediates in the pathway, such as Get2 and/or Get1 bound to the Get3–TA complex, are still unavailable, and the mechanisms by which Get1/2 remodels the Get3–TA complex and inserts the TA into the membrane remain unclear. Further, the structural basis for regulation of Get3's ATPase activity by Get4/5 and the TA substrate remains to be elucidated. Finally, it is unclear whether additional upstream components are required to help load newly synthesized TA proteins onto Sgt2, and if so, how these substrate relay events are accomplished.
    Comparison of SRP–SR with Get3: Common Regulatory Principles? Although the details of the SRP and GET pathways differ significantly, many similarities between the Get3 ATPase dimer and the SRP–SR GTPase dimer emerge from available data. In Dihydrotestosterone to the classical ‘GTPase switch’ paradigm, both SRP and GET systems forego the use of nucleotide exchange and the recruitment of external GEFs and GAPs as major regulatory elements. In support of the initial proposal by Gasper et al.[9], both systems use dimers as the functional unit. Further, multiple ‘on’ states can be generated within the dimer. Both the SRP–SR GTPase dimer and the Get3 ATPase dimer undergo an ordered series of conformational changes on the global (‘open’→‘closed’ transitions) and local (catalytic loop adjustments) scale to generate multiple, discrete functional states during their NTPase cycle. Each rearrangement provides a distinct regulatory point at which SRP–SR or Get3 can directly communicate with upstream and downstream effector molecules in the pathway. The author suggests that these dimeric nucleotide hydrolases provide ‘multistate navigator’ systems that use their conformational plasticity to ensure the spatiotemporal accuracy of diverse molecular actions required for cellular pathways. What drove the evolution of these regulatory proteins? To answer this question, it is useful to reflect on the bimodal nature of the classic ‘GTPase switch’. Ras-type GTPases often have a well-defined ‘on’ state in which they interact with effector molecules. By contrast, it is difficult to define a single ‘on’ or ‘off’ state for SRP–SR and Get3, as the pathways mediated by these proteins require a complex series of molecular events for which different functions must be turned ‘on’ or ‘off’ at distinct stages. For example, SRP and Get3 must effectively capture cargo proteins in the cytosol but promptly release them at the target membrane. SRP and SR must efficiently assemble a complex at early stages of targeting but promptly dissociate at the end of the targeting cycle. Effector interactions for Get3 is particularly complex, as this ATPase must bind three effector proteins, Get4, Get2, and Get1, in an ordered cascade [69]. The ability of SRP–SR and Get3 to adopt multiple conformations is necessary to drive these cyclic processes during which the substrate and various effector molecules must bind and later release in a sequential and controlled manner. Probably, modulation of the dimer interface provides a facile mechanism to increase conformational diversity, which might be particularly suitable for generating a multitude of conformational states required by these processes.