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.

We determined four X-ray structures of a representative member, GIMAP2, in different nucleotide-loading states. 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 signalling 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-localising 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. 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.



Schwefel D., Fröhlich C., Eichhorst J., Wiesner B., Behlke J., Aravind L, Daumke O. (2010) Structural basis of oligomerization in septin-like GIMAP2. PNAS 107, 20299-304.


Schwefel D., Arasu B.S., Marino S., Lamprecht B., Köchert K., Rosenbaum E., Eichhorst J., Wiesner B., Behlke J., Rocks O., Mathas  S., Daumke O. (2013) Structural insights into the mechanism of GTPase activation in the GIMAP family. Structure 21, 550-9.


Researcher in my group

David Schwefel (PhD 2011), Arasu B.S. (PhD student)



L. Aravind (NIH Washington), Stephan Mathas (MDC)

Figure 1: a) Crystal structure of the nucleotide-free GIMAP2 monomer. b) We proposed that GIMAP2 assembles in the GTP-bound state via two distinct interfaces forming a membrane-associated protein scaffold. This GIMAP2 scaffold might be disassembled by GIMAP7 which can stimulate the GTPase activity of GIMAP2.