GRAM domain containing 1B, also known as

GRAMD1B GRAM domain containing 1B, also known as GRAMD1B, Aster-B and KIAA1201, is a cholesterol transport protein that is encoded by the ''GRAMD1B'' gene. It contains a Transmembrane protein, transmembrane region and two Protein domain, domains of know ...

, Aster-B and KIAA1201, is a

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

transport

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that is encoded by the ''GRAMD1B''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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 me ...

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 a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

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

Homologs Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same loci, where they provide points along each chromosome th ...

(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 and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

, 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 sequence ...

. 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 can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comp ...

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 A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...

. 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 electric charge, electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). Howe ...

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 spec ...

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 In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (pronounced ...

site is located directly after the VASt domain. The proteins secondary structure consists of

alpha-helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

, 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 chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In 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 speci ...

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

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

bird Birds are a group of warm-blooded vertebrates constituting the class (biology), class Aves (), characterised by feathers, toothless beaked jaws, the Oviparity, laying of Eggshell, hard-shelled eggs, a high Metabolism, metabolic rate, a fou ...

fish A fish (: fish or fishes) is an aquatic animal, aquatic, Anamniotes, anamniotic, gill-bearing vertebrate animal with swimming fish fin, fins and craniate, a hard skull, but lacking limb (anatomy), limbs with digit (anatomy), digits. Fish can ...

and

invertebrate Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordata, chordate s ...

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

but is not as high as Cytochrome C. Phylogeny of gramd1b

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 or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

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 t ...

(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 organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...

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 () are yellow, orange, and red organic compound, organic pigments that are produced by plants and algae, as well as several bacteria, archaea, and Fungus, 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 An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...

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

SNPs In genetics and bioinformatics, 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 ...

from

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...

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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