ARHGAP11B

ARHGAP11B
Identifiers
Aliases	ARHGAP11B , B'-T, FAM7B1, Rho GTPase activating protein 11B, GAP (1-8), ArhGAP11B and human encephalisation
External IDs	OMIM: 616310; GeneCards: ARHGAP11B; OMA:ARHGAP11B - orthologs
Gene location (Human)
Chr.	Chromosome 15 (human)
End	30,649,529 bp
RNA expression pattern
	Top expressed in
	testicle; ; bone marrow; ; bone marrow cells; ; ganglionic eminence; ; stromal cell of endometrium; ; ventricular zone; ; gonad; ; lymph node; ; monocyte; ; appendix;
	n/a
	More reference expression data
	n/a
Gene ontology
Molecular function	GTPase activator activity ;
Cellular component	cytosol ;
Biological process	regulation of small GTPase mediated signal transduction ; signal transduction ; cerebral cortex development ; positive regulation of GTPase activity ;
	Sources:Amigo / QuickGO
Orthologs
	89839
	n/a
	ENSG00000274734 ; ENSG00000286139 ; ENSG00000285077
	n/a
	Q3KRB8
	n/a
	NM_001039841
	n/a
	NP_001034930
	n/a
	Wikidata
View/Edit Human

Last updated September 28, 2024

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.^[3]

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.^[3]

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.^[4] It has been reported^[5] 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.^[6] 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".^[7]

A 2020 study found that when ARHGAP11B was introduced into the primate common marmoset, it increased radial glial cells, upper layer neurons, and brain wrinkles (gyral and sulcus structures), leading to the expansion of the neocortex.^[8] This revealed that ARHGAP11B is the gene responsible for the development of the neocortex during human evolution.

Related Research Articles

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of neural integration in the central nervous system, and plays a key role in attention, perception, awareness, thought, memory, language, and consciousness. The cerebral cortex is the part of the brain responsible for cognition.

Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene. FOXP2 is a member of the forkhead box family of transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed in the brain, heart, lungs and digestive system.

Protein engineering is the process of developing useful or valuable proteins through the design and production of unnatural polypeptides, often by altering amino acid sequences found in nature. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles. It has been used to improve the function of many enzymes for industrial catalysis. It is also a product and services market, with an estimated value of $168 billion by 2017.

Thermogenin is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.

GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549. HRas is a small G protein in the Ras subfamily of the Ras superfamily of small GTPases. Once bound to Guanosine triphosphate, H-Ras will activate a Raf kinase like c-Raf, the next step in the MAPK/ERK pathway.

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

Thy-1 or CD90 is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

Adenine nucleotide translocator (ANT), also known as the ADP/ATP translocase (ANT), ADP/ATP carrier protein (AAC) or mitochondrial ADP/ATP carrier, exchanges free ATP with free ADP across the inner mitochondrial membrane. ANT is the most abundant protein in the inner mitochondrial membrane and belongs to the mitochondrial carrier family.

Transketolase-like-1 (TKTL1) is a gene closely related to the transketolase gene (TKT). It emerged in mammals during the course of evolution and, according to the latest research findings, is considered one of the key genes that distinguishes modern humans from Neanderthals. However, some modern humans also exhibit the "archaic" transketolase-like-1 allele attributed to Neanderthals, with no known effects.

ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.

The evolution of the brain refers to the progressive development and complexity of neural structures over millions of years, resulting in the diverse range of brain sizes and functions observed across different species today, particularly in vertebrates.

Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene.

Gyrification is the process of forming the characteristic folds of the cerebral cortex.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

ADP/ATP translocase 3, also known as solute carrier family 25 member 6, is a protein that in humans is encoded by the SLC25A6 gene.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

References

1 2 3 ENSG00000286139, ENSG00000285077 GRCh38: Ensembl release 89: ENSG00000274734, ENSG00000286139, ENSG00000285077 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
1 2 Florio M, Albert M, Taverna E, Namba T, Brandl H, Lewitus E, et al. (March 2015). "Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion". Science. 347 (6229): 1465–1470. Bibcode:2015Sci...347.1465F. doi: 10.1126/science.aaa1975 . PMID 25721503. S2CID 34506325.
↑ Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, et al. (September 2015). "NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse". Molecular Psychiatry. 20 (9): 1120–1131. doi: 10.1038/mp.2015.42 . PMID 25869807. S2CID 21934291.
↑ Namba T, Dóczi J, Pinson A, Xing L, Kalebic N, Wilsch-Bräuninger M, et al. (March 2020). "Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis". Neuron. 105 (5): 867–881.e9. doi: 10.1016/j.neuron.2019.11.027 . PMID 31883789.
↑ "'Breakthrough' finding shows how modern humans grow more brain cells than Neanderthals". Science. Retrieved 19 October 2022.
↑ Florio M, Namba T, Pääbo S, Hiller M, Huttner WB (December 2016). "A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification". Science Advances. 2 (12): e1601941. Bibcode:2016SciA....2E1941F. doi:10.1126/sciadv.1601941. PMC 5142801 . PMID 27957544.
↑ Michael Heide, Christiane Haffner, Ayako Murayama, Yoko Kurotaki, Haruka Shinohara, Hideyuki Okano, Erika Sasaki and Wieland B. Huttner. Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset, SCIENCE,18 Jun 2020, Vol 369, Issue 6503, pp. 546-550, DOI: 10.1126/science.abb2401