Biology:ARHGAP11B
 Generic protein structure example |
ARHGAP11B is a human-specific gene that amplifies basal progenitors, controls neural progenitor proliferation, and contributes to 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.[1]
Structure
ARHGAP11B encodes 267 amino acids. A truncated copy of ARHGAP11A, which is found throughout the animal kingdom and encodes a Rho GTPase-activating-protein (RhoGAP domain), ARHGAP11B comprises most of the GAP domain (until lysine-220), followed by a novel C-terminal sequence that lacks the 756 C-terminal 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.[1]
Function
ARHGAP11B is involved in neocortex folding; however, its precise function remains unknown. Several genes involved in intellectual disability encode proteins with RhoGAP domains or other proteins in the Rho signalling pathway.[2] It has been reported[3] 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, most likely due to the ability of mitochondria to sequester calcium, thereby activating mitochondrial matrix dehydrogenases in the citric acid cycle, particularly the oxoglutarate dehydrogenase complex.[citation needed]
Human evolution
Changes in ARHGAP11B are one of several key genetic factors of recent brain evolution and difference of modern humans to (other) apes and Neanderthals.[4] A 2016 study suggests, one mutation, a "single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex".[5]
References
- ↑ 1.0 1.1 "Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion". Science 347 (6229): 1465–1470. March 2015. doi:10.1126/science.aaa1975. PMID 25721503. Bibcode: 2015Sci...347.1465F.
- ↑ "NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse". Molecular Psychiatry 20 (9): 1120–1131. September 2015. doi:10.1038/mp.2015.42. PMID 25869807.
- ↑ "Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis". Neuron 105 (5): 867–881.e9. March 2020. doi:10.1016/j.neuron.2019.11.027. PMID 31883789.
- ↑ "'Breakthrough' finding shows how modern humans grow more brain cells than Neanderthals" (in en). Science. https://www.science.org/content/article/breakthrough-finding-shows-how-modern-humans-grow-more-brain-cells-neanderthals.
- ↑ "A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification". Science Advances 2 (12): e1601941. December 2016. doi:10.1126/sciadv.1601941. PMID 27957544. Bibcode: 2016SciA....2E1941F.
Further reading
- "Diversity of human copy number variation and multicopy genes". Science 330 (6004): 641–646. October 2010. doi:10.1126/science.1197005. PMID 21030649. Bibcode: 2010Sci...330..641S.
- "Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility". The EMBO Journal 40 (13): e107093. July 2021. doi:10.15252/embj.2020107093. PMID 33938018.
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