Gram domain containing 1b

GRAMD1B, also known as KIAA1201, is located in the human genome at 11q24.1.[9] It is located on the + strand and is flanked by a variety of other genes. It spans 269,347 bases.[5]

GRAMD1B and surrounding genes

The most verified isoform, isoform 1, contains 21 exons. There are four validated isoform variants of human GRAMD1B.[5] These consist of truncated 5’ and 3’ regions, resulting in the loss of an exon. One prominent analysis of the mouse gene predicts one form of Gramd1b that is 699 amino acids long.[8]

GRAMD1B is an integral membrane protein that contains several domains, motifs and signals.

GRAMD1B protein structure

Structure

The protein contains four dileucine motifs, three located within or close to the GRAM domain.[17] A predicted leucine zipper pattern extends through a majority the transmembrane region though it is not a nuclear protein.[17] A SUMOylation site is located directly after the VASt domain.[18] The proteins secondary structure consists of alpha-helices, beta-strands and coils.[19] Beta-strands are mainly located within the two domains, while the alpha-helixes are concentrated near the transmembrane region. Three disulfide bonds are predicted throughout the protein.[20]

Predicted alpha-helix structure of GRAMD1B transmembrane region.[21]

Predicted 3D structure of GRAMD1B,[19]

GRAMD1B is expressed in a variety of tissues. It is most highly expressed in the gonadal tissue, adrenal gland, brain and placenta.[8][7][22] It has raised expression rates in adrenal tumors, lung tumors. Developmentally, it is most highly expressed during infancy. The EST profile is supported with experimental data from multiple sources[23]

GRAMD1B expression in a variety of tissues.[22]

[22] Tissue expression of GRAMD1B

When the plasma membrane contains high levels of cholesterol, GRAMD1b as well as GRAMD1a and GRAMD1c move to sites of contact between the plasma membrane and the endoplasmic reticulum.[8] GRAMD1 proteins then facilitate the transport of cholesterol into the endoplasmic reticulum.[7][8] In the case of GRAMD1b, the plasma membrane source of cholesterol is high-density lipoprotein (HDL).[7][8] The VASt domain is responsible for binding cholesterol while the GRAM domain determines the location of the protein through sensing of cholesterol and binding partially negatively charged lipids in the plasma membrane, especially phosphatidylserine.[8][26]

GRAMD1b is also implicated in transporting carotenoids within the cell.[27]

Mutations and other genetic studies link GRAMD1B to neurodevelopmental disorders, such as intellectual disability and schizophrenia.[7] Loss of GRAMD1b results in reduced cholesterol storage in the adrenal gland and serum corticosterone levels in mice.[7] Reduction of GRAMD1B and GRAMD1C suppresses the onset of a form of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH) in mice.[7]

A study tagging SNPs from chronic lymphocytic leukemia found GRAMD1B to be the second strongest risk allele region.[30] This association is supported through a number of studies[31][32] The aberrant tri-methylation of histone H3 lysine 27 induces inflammation and has been shown to increase GRAMD1B levels in colon tumors.[33]