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  • br Conflict of interest br Acknowledgements br A Class

    2022-06-22


    Conflict of interest
    Acknowledgements
    A Class of Unconventional, Dimerization-Activated GTPases GTP-binding proteins, or GTPases, are a superfamily of proteins that regulate numerous cellular pathways 1, 2, 3, 4. Pioneering work on the extended Ras subfamily of GTPases, exemplified by Ras, Rho, Rab, Arf, and heterotrimeric GTPases, has established a ‘GTPase switch’ paradigm to explain their regulatory mechanism 5, 6. In this paradigm, GTPases alternate between a GDP-bound inactive conformation and a GTP-bound active conformation in which they interact with A-674563 molecules to trigger cellular responses. A key to this mechanism is the temporal separation of the GTP and GDP states in these proteins due to their intrinsically slow rates of nucleotide exchange and GTP hydrolysis. Thus, interconversion between these states requires the recruitment of external factors, such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), to turn these GTPases ‘on’ and ‘off’, respectively. Additional layers of regulation can be exerted, such as through guanine nucleotide dissociation inhibitors that further stabilize the GDP state [7]. Nevertheless, these mechanisms are conceptually extensions of the bimodal regulatory mechanism established by the classic paradigm. Despite the importance of Ras-type GTPases, analyses of the evolutionary history of the P-loop GTPases and related ATPases suggested a much larger repertoire of proteins that use the energy from nucleotide triphosphates to regulate cellular processes (Figure 1, Key Figure) [8]. As shown by Leipe et al. [8], the GTPase superclass underwent seven evolutionary diversifications after the ancestral GTPase (Figure 1, yellow circles) and can be divided into two large classes. The translation factors (TRAFAC) class includes proteins involved in translation, signal transduction, and cell motility. The signal recognition particle (SRP), MinD, and BioD (SIMIBI) class includes the SRP54 and SRP receptor (SR) GTPases and MinD-like ATPases involved in protein localization, chromosome partitioning, and membrane transport. Notably, the extended Ras subfamily is a small subset of GTPases in the TRAFAC class that emerged after the last evolutionary diversification (Figure 1, blue). Compared with Ras-type GTPases, the SIMIBI class of nucleotide hydrolases displays distinct biochemical, structural, and dynamic properties, and the regulatory mechanisms of this class of nucleotide hydrolases are far less understood. A notable feature of the SIMIBI class of GTPases and related ATPases is their ability to form dimers (Figure 1A, red, and Figure 1B–H). As proposed by Gasper et al. [9], many G proteins are activated by nucleotide-dependent dimerization and can be functionally grouped into a class that uses regulatory mechanisms distinct from the ‘GTPase switch’ paradigm. Readers are referred to the reviews by Gasper et al. [9] for a more comprehensive summary of G-protein systems (within and beyond the SIMIBI family) that might fall into this class, and Bange and Sinning [10] for a detailed description of the structural features of the SIMIBI family GTPases. A major gap in understanding has been the mechanism by which the dimerization-governed nucleotide hydrolase cycles of these proteins are coupled to biological function. This review summarizes recent findings from two of the best-characterized systems, the SRP/SR GTPase dimer and the Get3 ATPase dimer, which mediate the co- and post-translational targeting of nascent proteins to cellular membranes, respectively. The results show that these proteins not only function as dimers but also generate multiple, functionally and structurally distinct conformational states in the dimer in an ordered sequence (hence the analogy to ‘tango’ as originally coined by Gasper et al.). Each state provides a point of regulation and/or fulfills a distinct function in the respective biological pathway. These observations suggest a novel mode of regulation that might be generalized to this class of dimeric nucleotide hydrolases.