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© Katharina Bohm / MDC

GTPases of the Immunity associated proteins (GIMAPs)

GTPases of the Immunity associated proteins comprise a septin-related GTPase family in humans. The seven GIMAP members are predominantly expressed in cells of the immune system. Some GIMAPs localize to the mitochondrial membrane and are proposed to regulate apoptosis by controlling the activity of Bcl2 proteins.

Scientific illustration

Figure: Structure of nucleotide-free GIMAP2 (pdb 2XTP) and model for the nucleotide-dependent assembly (based on pdb 2XTN).

We determined four X-ray structures of a representative member, GIMAP2, in different nucleotide-loading states (Schwefel et al., PNAS, 2010). In combination with biochemical experiments, this work elucidated the molecular basis of GTP-dependent oligomerization via the GTPase domains. Interestingly, the dimerization mode was similar to that of dynamin GTPases, suggesting a common evolutionary ancestor of dynamin and septin proteins. We also showed that in Jurkat cells, GIMAP2 is located at the surface of lipid droplets which are cellular storage and signaling compartments. Interestingly, GIMAP2 binds GTP with high affinity but does not hydrolyze it.

To understand how GTP hydrolysis is activated and the GIMAP2 scaffold disassembled, we screened for other GIMAP members co-localizing with GIMAP2 at lipid droplets and identified GIMAP7. In contrast to GIMAP2, GIMAP7 displayed dimerization-stimulated GTP hydrolysis. The crystal structure of GTP-bound GIMAP7 showed a homo-dimer which assembled via the GTPase domains, with the long helical extensions protruding in opposite directions (Schwefel et al., Structure, 2013). We identified a catalytic arginine which is supplied to the opposing monomer to stimulate GTP hydrolysis. GIMAP7 also efficiently stimulated GTP hydrolysis of GIMAP2 via an analogous mechanism. Strikingly, we found GIMAP2 and GIMAP7 differentially down-regulated in several human T cell lymphoma lines. Our findings suggest a classification of GIMAPs into a membrane-anchored anti-apoptotic subgroup forming GTP-dependent scaffolds, and a cytosolic pro-apoptotic subgroup regulating scaffold assembly.

In a collaborative effort, we recently contributed biochemical insights to understand the role of GIMAP6 during autophagy and inflammation (Yao et al., J Exp Med, 2022).

 

Publications

  1. Schwefel, D., Frohlich, C., Eichhorst, J., Wiesner, B., Behlke, J., Aravind, L., and Daumke, O. (2010). Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2). PNAS 107, 20299-20304. https://doi.org/10.1073/pnas.1010322107.
  2. Schwefel, D., Arasu, B.S., Marino, S.F., Lamprecht, B., Kochert, K., Rosenbaum, E., Eichhorst, J., Wiesner, B., Behlke, J., Rocks, O., et al. (2013). Structural insights into the mechanism of GTPase activation in the GIMAP family. Structure 21, 550-559. https://doi.org/10.1016/j.str.2013.01.014.
  3. Yao, Y., Du Jiang, P., Chao, B.N., Cagdas, D., Kubo, S., Balasubramaniyam, A., Zhang, Y., Shadur, B., NaserEddin, A., Folio, L.R., et al. (2022). GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans. J Exp Med 219. https://doi.org/10.1084/jem.20201405.

 

Researcher in my group

David Schwefel (Doctoral student 2007 - 2011)

Arasu Balasubramaniyam (Doctoral student 2011 - 2016)

 

Main collaborations

Michael J Lenardo, NIH

Stephan Mathas, MDC