Biology:ArhGAP11B and human encephalisation

ARHGAP11B is a human-specific gene which appeared after the divergence from chimpanzees. It amplifies basal progenitors, controls neural progenitor proliferation and can cause neocortex folding. It is capable of causing neocortex folding in mice. This likely reflects a role for ARHGAP11B in development and evolutionary expansion of the human neocortex, a conclusion consistent with the finding that the gene duplication that created ARHGAP11B occurred on the human lineage after the divergence from the chimpanzee lineage but before the divergence from Neanderthals.

Structure

ARHGAP11B encodes 267 amino-acids and is a truncated version of ARHGAP11A. ARHGAP11B arose on the human evolutionary lineage after the divergence from the chimpanzee lineage by partial duplication of ARHGAP11A, which is found throughout the animal kingdom and encodes a Rho GTPase-activating-protein (RhoGAP domain). ARHGAP11B exists not only in present-day humans but also in Neandertals and Denisovans. ARHGAP11B comprises most of the GAP-domain (until lysine-220) followed by a novel C-terminal sequence but lacking the C-terminal 756 amino acids of ARHGAP11A.

Activity

In contrast to full-length ARHGAP11A and ARHGAP11A 1-250, ARHGAP11B, like ARHGAP11A1-220, did not exhibit RhoGAP activity in a RhoA/Rho-kinase–based cell transfection assay. This indicates that the C-terminal 47 amino-acids of ARHGAP11B (after lysine-220) constitute not only a unique sequence, resulting from a frameshifting deletion, but also are functionally distinct from their counterpart in ARHGAP11A. In this assay, co-expression of ARHGAP11B along with ARHGAP11A did not inhibit the latter's RhoGAP activity.

Function

Since several genes involved in mental retardation encode proteins with RhoGAP domains or other proteins in the Rho signalling pathway it does not come as a complete surprise that ARHGAP11B is involved in neocortex folding; however, its precise function is still unknown. It has been reported that it is located in mitochondria where it binds to the adenine nucleotide translocator; it does not affect the adenine nucleotide exchange activity of the translocator, but it does lead to delayed opening of the mitochondrial permeability transition pore, thus allowing for greater sequestration of calcium. Furthermore, the presence of ARHGAP11B in the mitochondria boosts glutaminolysis, which is most likely due to the ability of mitochondria to sequester more calcium which activates mitochondrial matrix dehydrogenases in the citric acid cycle, particularly the oxoglutarate dehydrogenase complex.

References

• Sudmant, P. H.; Kitzman, J. O.; Antonacci, F.; Alkan, C.; Malig, M.; Tsalenko, A.; Sampas, N.; Bruhn, L. et al. (2010). "1000 Genomes Project, Diversity of human copy number variation and multicopy genes". Science 330 (6004): 641–646. doi:10.1126/science.1197005. PMID 21030649.