ARHGAP11B

Description

The ARHGAP11B (Rho GTPase activating protein 11B) is a protein-coding gene located on chromosome 15.

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.

== 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.

== 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. 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.

ARHGAP11B is a hominin-specific protein that plays a key role in the development and evolutionary expansion of the brain neocortex. It promotes the amplification of basal progenitors in the subventricular zone, leading to increased neuron production during fetal corticogenesis and contributing to neocortex expansion. This function is achieved by inhibiting the mitochondrial permeability transition pore (mPTP) through interaction with ADP:ATP translocase, which delays the opening of the mPTP. This delay increases mitochondrial Ca(2+) concentration and induces glutamine catabolism, both essential for basal progenitor proliferation. Interestingly, ARHGAP11B lacks GTPase activator activity, which is crucial for promoting basal progenitor amplification during neocortex development. This protein interacts with components of the ADP:ATP translocase, including SLC25A4/ANT1 and SLC25A5/ANT2.

ARHGAP11B is also known as B'-T, FAM7B1, GAP (1-8).

Associated Diseases

WES Whole Exome Sequencing