GRAM domain containing 1B, also known as GRAMD1B and KIAA1201, is a protein that is encoded by the GRAMD1B gene.[1] It contains a transmembrane region and two domains of known function; the GRAM domain and a VASt domain. It is predicted to localize in the nucleus, supported by several nuclear transport signals and nuclearly associated motifs. This highly conserved gene is found in a variety of vertebrates and invertebrates, however is not found in bacteria or fungi.[2]
GRAMD1B, also known as KIAA1201, is located in the human genome at 11q24.1.[3] It is located on the + strand and is flanked by a variety of other genes. It spans 269,347 bases.[1]
The most verified isoform, isoform 1, contains 21 exons. There are four validated isoform variants of human GRAMD1B.[1] These consist of truncated 5’ and 3’ regions, resulting in the loss of an exon.
Isoform
mRNA length (bp)
Exons
Protein length (aa)
Status
1
7927
21
745
Validated
2
7906
20
738
Validated
3
7636
20
698
Validated
4
7561
20
694
Validated
Protein
GRAMD1B contains several domains, motifs and signals.
There are two confirmed domains within GRAMD1B. The protein gets its name from the GRAM domain, located approximately 100 amino acids from the start codon. The GRAM domain is commonly found in myotubularin family phosphatases and predominantly involved in membrane coupled processes.[4] GRAMD1B also contains the VASt (VAD1 Analog of StAR-related lipid transfer) domain. The VASt domain is predominantly associated with lipid binding domains, such as GRAM. It is most likely to function in binding large hydrophobic ligands and may be specific for sterol.[5]
Composition Features
There are two negative charge clusters, located from amino acids 232-267 and 348-377.[6] The first cluster is not highly conserved, nor is it located in a motif or domain. The second cluster is located directly before the VASt domain and is conserved.
There are three repeat sequence regions, all fairly conserved in orthologs.[6]
The mature protein contains two nuclear localization signals, pat4 and pat7.[9] There are four dileucine motifs, three located within or close to the GRAM domain.[9] A leucine zipper pattern extends through a majority the transmembrane region.[9] A SUMOylation site is located directly after the VASt domain.[10] The proteins secondary structure consists of alpha-helices, beta-strands and coils.[11] 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.[12]
GRAMD1B is predicted to localize in the nucleus and contains a transmembrane domain, most likely placing it in the membrane of the nucleus.[6]
Expression
GRAMD1B is expressed in a variety of tissues. It is most highly expressed in the gonadal tissue, adrenal gland, brain and placenta.[14] 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[15]
GRAMD2 diverged earliest in history while the most recent split is GRAMD1A. The GRAMD1B gene’s rate of divergence significantly faster than Fibrinogen but is not as high as Cytochrome C.
Adapter protein associated with regulating nuclear transport to the cytoplasm
nuclear
Clinical significance
A study tagging SNPs from chronic lymphocytic leukemia found GRAMD1B to be the second strongest risk allele region.[19] This association is supported through a number of studies[20][21] The aberrant tri-methylation of histone H3 lysine 27 induces inflammation and has been shown to increase GRAMD1B levels in colon tumors.[22] A variant of GRAMD1B, characterized by the amino acid substitution S601P, has been associated with increased susceptibility to multiple sclerosis.[23]
