A Novel Class of Dimerization-activated GTPases

For over two decades, GTPases have been described as two-state, ‘on-off’ switches governed by the ‘GTPase switch’ paradigm. In contrast, our work on the SRP and GET pathways revealed a novel mechanism of regulation wherein dimeric GTPases or ATPases use multiple, discrete conformational rearrangements in their dimerization cycle to directly sense and respond to biological signals, and thus turn ‘on’ and turn ‘off’ the correct molecular events. These new principles of molecular recognition and regulation can be generalizable to a growing class of nucleotide hydrolases that control numerous cellular processes.

Multiple Members of the SIMIBI GTPase Family Form Dimers

(A) Inferred evolutionary history of GTPase families; adapted from Figure 1 in Leipe et al. 2002, J. Mol. Biol. Numbered circles indicate various evolutionary events associated with the diversification of GTPases. Broken lines denote uncertainty in the exact point of origin of the lineage. Dashed ellipses group the lineages from within which a new lineage potentially could have emerged. Members of the extended Ras subfamily are in blue, members of the SIMIBI family known to form dimers are in red. (B–H) Top view of the structures of dimeric GTPases and ATPases in the SIMIBI family, including SRP54 and SR (B; 1RJ9), FlhG (C; 4RZ3), MinD (D; 3Q9I), NIfH (E; 1N2C), Get3 (F; 2WOJ), HypB (G; 2HF8), and PurA (H; 4M9D). The bound nucleotides are in spacefill. SIMIBI, signal recognition particle (SRP), MinD, and BioD; SR, signal recognition particle receptor; SRP, signal recognition particle.

Recommended Readings:

  • Shan, S.O.* (2016) Trends Biochem. Sci. “ATPase and GTPase Tangos drive intracellular protein transport”. PMID: 27658684.
  • Shan, S.O., Schmidt, S., and Zhang, X. (2009) Biochemistry 48, 6696-6704. “Signal recognition particle (SRP) and SRP receptor: a new paradigm for multistate regulatory GTPases.” PMID: 19469550.