GRAM domain containing 1B, also known as GRAMD1B, Aster-B and KIAA1201, is a

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...

transport

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that is encoded by the GRAMD1B

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. It contains a

transmembrane region Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral ...

and two domains of known function; the

GRAM domain The GRAM domain is found in glucosyltransferases, myotubularins and other membrane-associated proteins. The structure of the GRAM domain is similar to that found in PH domains. Proteins containing GRAM domains are found in all eukaryotes and b ...

and a VASt domain. It is anchored to the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

. This highly conserved gene is found in a variety of vertebrates and invertebrates.

Homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...

(Lam/Ltc proteins) are found in yeast.

Gene

GRAMD1B, also known as KIAA1201, is located in the human genome at 11q24.1. It is located on the + strand and is flanked by a variety of other genes. It spans 269,347 bases. GRAMD1B_Gene_Region

mRNA

The most verified

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

, isoform 1, contains 21 exons. There are four validated isoform variants of human GRAMD1B. These consist of truncated 5’ and 3’ regions, resulting in the loss of an

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...

. One prominent analysis of the mouse gene predicts one form of Gramd1b that is 699 amino acids long.

Protein

GRAMD1B is an

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...

that contains several domains, motifs and signals. GRAMd1b structure

Domains

There are two confirmed cytoplasmic domains within GRAMD1B. The protein gets its name from the

, 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. 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 Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the g ...

. A C-terminal domain in GRAMD1B sits within the lumen of the ER, is predicted to have alpha-helical secondary structure, and is modified by tryptophan C-mannosyaltion.

Composition Features

There are two negative charge clusters, located from amino acids 232-267 and 348-377. 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. Molecular weight and

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also ...

are conserved in

orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spe ...

Structure

The protein contains four dileucine motifs, three located within or close to the GRAM domain. A predicted leucine zipper pattern extends through a majority the transmembrane region though it is not a nuclear protein. A SUMOylation site is located directly after the VASt domain. The proteins secondary structure consists of

alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earli ...

, beta-strands and coils. Beta-strands are mainly located within the two domains, while the alpha-helixes are concentrated near the transmembrane region. Three

disulfide bonds In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

are predicted throughout the protein. Predicted_alpha-helix_structure_of_GRAMD1B_transmembrane_region

Subcellular location

GRAMD1B is anchored to in the endoplasmic reticulum by a transmembrane domain.

Expression

GRAMD1B is expressed in a variety of tissues. It is most highly expressed in the gonadal tissue, adrenal gland, brain and placenta. 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 GRAMD1B_expression_in_a_variety_of_tissues

Homology

Orthologs

The

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spe ...

space for GRAMD1B spans a large portion of evolutionary time. GRAMD1B can be found in mammals,

bird Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...

fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% ...

and

invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

s. Homologous proteins (Lam/Ltc) are found in yeast.

Paralogs

There are four paralogs of GRAMD1B. The most closely related is GRAMD1A while the most distant ortholog is GRAMD2A/GRAMD2.

Phylogeny

GRAMD2 diverged earliest in history while the most recent split is GRAMD1A. The GRAMD1B gene’s rate of divergence significantly faster than

Fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...

but is not as high as

Cytochrome C The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

Function

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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

and the endoplasmic reticulum. GRAMD1 proteins then facilitate the transport of cholesterol into the endoplasmic reticulum. In the case of GRAMD1b, the plasma membrane source of cholesterol is

high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules ( lipids) around the body within the water outside cells. They are ...

(HDL). 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 Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...

in the plasma membrane, especially

phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via a ...

. GRAMD1b is also implicated in transporting

carotenoids Carotenoids (), also called tetraterpenoids, are yellow, orange, and red organic pigments that are produced by plants and algae, as well as several bacteria, and fungi. Carotenoids give the characteristic color to pumpkins, carrots, parsnips, ...

within the cell.

Protein interactions

Several different proteins have been experimentally confirmed or predicted to interact with GRAMD1B.

Clinical significance

Mutations and other genetic studies link GRAMD1B to neurodevelopmental disorders, such as intellectual disability and schizophrenia. Loss of GRAMD1b results in reduced cholesterol storage in the adrenal gland and serum corticosterone levels in mice. Reduction of GRAMD1B and GRAMD1C suppresses the onset of a form of

non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...

, non-alcoholic steatohepatitis (NASH) in mice. A study tagging

SNPs In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

from

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, n ...

found GRAMD1B to be the second strongest risk allele region. This association is supported through a number of studies The aberrant tri-methylation of histone H3 lysine 27 induces inflammation and has been shown to increase GRAMD1B levels in colon tumors.

References

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