Gram domain containing 1b

Last updated

GRAMD1B
Identifiers
Aliases GRAMD1B , GRAM domain containing 1B, LINC01059, Aster-B
External IDs MGI: 1925037; HomoloGene: 18223; GeneCards: GRAMD1B; OMA:GRAMD1B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57476

235283

Ensembl

ENSG00000023171

ENSMUSG00000040111

UniProt

Q3KR37

Q80TI0

RefSeq (mRNA)

NM_001286563
NM_001286564
NM_020716
NM_001330396

RefSeq (protein)
Location (UCSC) Chr 11: 123.36 – 123.63 Mb Chr 9: 40.29 – 40.53 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

GRAM domain containing 1B, also known as GRAMD1B, Aster-B and KIAA1201, is a cholesterol transport protein that is encoded by the GRAMD1B gene. [5] [6] [7] [8] It contains a transmembrane region and two domains of known function; the GRAM domain and a VASt domain. It is anchored to the endoplasmic reticulum. [7] This highly conserved gene is found in a variety of vertebrates and invertebrates. Homologs (Lam/Ltc proteins) are found in yeast. [7]

Gene

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 GRAMD1B Gene Region.png
GRAMD1B and surrounding genes

mRNA

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]

IsoformmRNA length (bp)ExonsProtein length (aa)Status
1792721745Validated
2790620738Validated
3763620698Validated
4756120694Validated

Protein

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

GRAMD1B protein structure GRAMd1b structure.png
GRAMD1B protein structure

Domains

There are two confirmed cytoplasmic 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. [10] 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. [11] A C-terminal domain in GRAMD1B sits within the lumen of the ER, is predicted to have alpha-helical secondary structure, [12] and is modified by tryptophan C-mannosyaltion. [13]

Composition Features

There are two negative charge clusters, located from amino acids 232-267 and 348-377. [14] 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. [14]

Repeat #Sets of RepeatsLength (aa)LocationSimilarity Score
1318Within first 100 amino acids83.44
2221GRAM domain77.22
3222VASt domain67.94

Molecular weight and isoelectric point are conserved in orthologs.

RegionAmino Acids [5] Isoelectric point [15] Molecular Weight (kdal) [16]
Human GRAMD1B745pH of 6.0286.5
GRAM domain94pH of 8.2711.3
VASt domain144pH of 9.4117.3
Transmembrane region21pH of 5.182.3

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. Predicted alpha-helix structure of GRAMD1B transmembrane region.png
Predicted alpha-helix structure of GRAMD1B transmembrane region.
Predicted 3D structure of GRAMD1B, Predicted 3D structure of GRAMD1B.png
Predicted 3D structure of GRAMD1B,

Subcellular location

GRAMD1B is anchored to in the endoplasmic reticulum by a transmembrane domain. [7] [8]

Expression

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. GRAMD1B expression in a variety of tissues.png
GRAMD1B expression in a variety of tissues.
Tissue expression of GRAMD1B Tissue Expression of GRAMD1B.png
Tissue expression of GRAMD1B

Homology

Orthologs

The ortholog space for GRAMD1B spans a large portion of evolutionary time. GRAMD1B can be found in mammals, bird, fish and invertebrates. Homologous proteins (Lam/Ltc) are found in yeast. [7]

Genus speciesCommon NameAccession NumberDate of Divergence (MYA) [24] Identity [25]
Homo sapiens HumanNP_001273492.10100.00%
Aotus nancymaae Nancy Ma's Night MonkeyXP_012325676.13.299.00%
Papio anubis Olive BaboonXP_017804515.129.4497.00%
Castor canadensis BeaverXP_020037170.19098.00%
Octodon degus DenguXP_004636450.19097.00%
Pantholops hodgsonii Tibetan AntelopeXP_005958036.19699.00%
Bos mutus Domestic YakXP_005896826.19698.00%
Tursiops truncatus DolphinXP_0197975439683.00%
Elephantulus edwardii Cape Elephant ShrewXP_006895663.110598.00%
Gallus gallus ChickenXP_015153638.131293.00%
Calypte anna Anna's Humming BirdXP_008490701.131291.00%
Pygoscelis adeliae Adelie PenguinXP_009331694.131291.00%
Coturnix japonica Japanese QuailXP_015739426.131290.00%
Anolis carolinensis Carolina AnoleXP_008111963.131287.00%
Danio rerio Zebra FishXP_009303888.143573.00%
Callorhinchus milii Australian Ghost SharkXP_007894251.147377.00%
Branchiostoma belcheri LanceletXP_019624725.168440.00%
Octopus bimaculoides California Two-Spot OctopusXP_014769036.179740.00%
Lingula anatina BrachiopodXP_01341557879738.00%
Zootermopsis nevadensis TermiteKDR17240.179737.00%
Trachymyrmex cornetzi AntXP_018362289.179734.00%

Paralogs

There are four paralogs of GRAMD1B. [25] The most closely related is GRAMD1A while the most distant ortholog is GRAMD2A/GRAMD2.

ParalogSequence LengthSequence Identity [25] Date of Divergence (MYA) [24]
GRAMD1A 724 aa46.60%421.0
GRAMD1C 662 aa37.90%934.7
GRAMD2B/GRAMD3491 aa18.50%1625.6
GRAMD2A353 aa16.70%1724.2

Phylogeny

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.

Phylogeny of GRAMD1B Phylogeny of gramd1b.png
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 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]

Protein interactions

Several different proteins have been experimentally confirmed or predicted to interact with GRAMD1B. [28] [29]

ProteinInteraction identified via [28] [29] FunctionLocation
COPAExperimentalBinds dilysine motifs. Required for budding from the Golgi and retrograde Golgi to ER transportsystolic
SPICE1Data MiningSpindle and centriole associated. Regulates centriole duplication, proper bipolar spindle formation and chromosome congregation in mitosisnuclear
GTPBP8Data Mining GTP binding protein unconfirmed
YwhaeCo-sedimentationAdapter protein associated with regulating nuclear transport to the cytoplasmnuclear

Clinical significance

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]

Related Research Articles

A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">SREBP cleavage-activating protein</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP, is a protein that in humans is encoded by the SCAP gene.

<span class="mw-page-title-main">Membrane-bound transcription factor site-1 protease</span> Mammalian protein found in Homo sapiens

Membrane-bound transcription factor site-1 protease, or site-1 protease (S1P) for short, also known as subtilisin/kexin-isozyme 1 (SKI-1), is an enzyme that in humans is encoded by the MBTPS1 gene. S1P cleaves the endoplasmic reticulum loop of sterol regulatory element-binding protein (SREBP) transcription factors.

<span class="mw-page-title-main">SOAT1</span> Protein-coding gene in the species Homo sapiens

Sterol O-acyltransferase 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.

<span class="mw-page-title-main">Oxysterol-binding protein</span>

The oxysterol-binding protein (OSBP)-related proteins (ORPs) are a family of lipid transfer proteins (LTPs). Concretely, they constitute a family of sterol and phosphoinositide binding and transfer proteins in eukaryotes that are conserved from yeast to humans. They are lipid-binding proteins implicated in many cellular processes related with oxysterol, including signaling, vesicular trafficking, lipid metabolism, and nonvesicular sterol transport.

<span class="mw-page-title-main">VAPA</span> Protein-coding gene in humans

VAMP-Associated Protein A is a protein that in humans is encoded by the VAPA gene. Together with VAPB and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes.

<span class="mw-page-title-main">OSBP</span> Protein-coding gene in the species Homo sapiens

Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene.

<span class="mw-page-title-main">SURF4</span> Protein-coding gene humans

Surfeit locus protein 4 or Surf4 is a protein involved in regulating export of some proteins from the endoplasmic reticulum to the golgi bodies. Surf4 is involved in trafficking soluble proteins, namely lipoproteins and PCSK9. It recognizes cargo proteins via a three-amino-acid sequence near the N-termini. The related protein in yeast is called Erv29p.

<span class="mw-page-title-main">STARD5</span> Protein-coding gene in the species Homo sapiens

StAR-related lipid transfer protein 5 is a protein that in humans is encoded by the STARD5 gene. The protein is a 213 amino acids long, consisting almost entirely of a StAR-related transfer (START) domain. It is also part of the StarD4 subfamily of START domain proteins, sharing 34% sequence identity with STARD4.

<span class="mw-page-title-main">FAM214A</span> Protein-coding gene in the species Homo sapiens

Protein FAM214A, also known as protein family with sequence similarity 214, A (FAM214A) is a protein that, in humans, is encoded by the FAM214A gene. FAM214A is a gene with unknown function found at the q21.2-q21.3 locus on Chromosome 15 (human). The protein product of this gene has two conserved domains, one of unknown function (DUF4210) and another one called Chromosome_Seg. Although the function of the FAM214A protein is uncharacterized, both DUF4210 and Chromosome_Seg have been predicted to play a role in chromosome segregation during meiosis.

<span class="mw-page-title-main">Tetratricopeptide repeat protein 39B</span> Protein-coding gene in the species Homo sapiens

Tetratricopeptide repeat protein 39B is a protein that in humans is encoded by the TTC39B gene. TTC39B is also known as C9orf52 or FLJ33868. The main feature within tetratricopeptide repeat 39B is the domain of unknown function 3808 (DUF3808), spanning the majority of the protein.

A FFAT motif is a protein sequence motif of six defined amino acids plus neighbouring residues that binds to proteins in the VAP protein family.

<span class="mw-page-title-main">Gram domain containing 1a</span> Protein that is encoded by the GRAMD1A gene

GRAM domain containing 1A also known as Aster-A is a protein that is encoded by the GRAMD1A gene. It contains a transmembrane region, a GRAM domain and a VASt domain that can bind cholesterol. GRAMD1A has four paralogs: GRAMD1B and GRAMD1C and two without VASt domains, GRAMD2A and GRAMD2B. These proteins are mammalian representatives of the yeast lipid transfer proteins anchored at a membrane contact site (LAM) family.

<span class="mw-page-title-main">Star related lipid transfer domain containing 3</span>

StAR related lipid transfer domain containing 3(STARD3) is a protein that in humans is encoded by the STARD3 gene. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport. STARD3 creates membrane contact sites between the endoplasmic reticulum (ER) and late endosomes where it moves cholesterol.

<span class="mw-page-title-main">GRAMD1C</span> Protein that is encoded by the GRAMD1C gene

GRAM domain containing 1C also known as Aster-C is a cholesterol transport protein that is encoded by the GRAMD1C gene. It contains a transmembrane region, a GRAM domain and a VASt domain. It is anchored to the endoplasmic reticulum through its transmembrane domain.

<span class="mw-page-title-main">Gram domain-containing 2A</span> Protein encoded by the GRAMD2A gene

GRAM domain-containing 2A protein is a protein encoded by the GRAMD2A gene. Like GRAMD2B, the protein consists of a GRAM domain and a transmembrane domain that anchors it to the endoplasmic reticulum.

<span class="mw-page-title-main">GRAM domain-containing 2B</span> Protein encoded by the GRAMD2B gene

GRAM domain-containing 2B protein, also known as NS3TP2 and HCV NS3-transactivated protein 2 is a protein encoded by the GRAMD2B gene.

VAD1 analog of StAR-related lipid transfer (VASt) is a steroidogenic acute regulatory protein‐related lipid transfer (StART)-like lipid-binding domain first identified in the vad1 protein in Arabidopsis thaliana. Proteins containing these domains are found in eukaryotes and usually contain another lipid-binding domain, typically the GRAM domain and sometimes the C2 domain in plants and the integral peroxisomal membrane peroxin Pex24p domain in oomycetes.

<span class="mw-page-title-main">TMEM212</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 212 is a protein that in humans is encoded by the TMEM212 gene. The protein consists of five transmembrane domains and localizes in the plasma membrane and endoplasmic reticulum. TMEM212 has orthologs in vertebrates but not invertebrates. TMEM212 has been associated with sporadic Parkinson's disease, facial processing, and adiposity in African Americans.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000023171 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040111 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 "Entrez Gene: GRAM domain containing 1B" . Retrieved 2017-02-19.
  6. ↑ "UniProtKB - Q3KR37 (ASTRB_HUMAN)" . Retrieved March 6, 2020.
  7. 1 2 3 4 5 6 7 8 9 10 11 Naito T, Saheki Y (August 2021). "GRAMD1-mediated accessible cholesterol sensing and transport". Biochim Biophys Acta Mol Cell Biol Lipids. 1866 (8): 158957. doi:10.1016/j.bbalip.2021.158957. PMID   33932585. S2CID   233477388.
  8. 1 2 3 4 5 6 7 8 Sandhu J, Li S, Fairall L, et al. (4 October 2018). "Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells". Cell. 175 (2): 514–529.e20. doi:10.1016/j.cell.2018.08.033. PMC   6469685 . PMID   30220461.
  9. ↑ "GRAMD1B Gene - GeneCards | GRM1B Protein | GRM1B Antibody". GeneCards Human Gene. Retrieved 2 May 2017.
  10. ↑ "GRAM Protein Domain".
  11. ↑ "PROSITE". prosite.expasy.org. Retrieved 2 May 2017.
  12. ↑ Naito T, Ercan B, Krshnan L, Triebl A, Koh DH, Wei FY, et al. (November 2019). "Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex". eLife. 8: e51401. doi: 10.7554/eLife.51401 . PMC   6905856 . PMID   31724953.
  13. ↑ John A, Järvå MA, Shah S, Mao R, Chappaz S, Birkinshaw RW, et al. (4 February 2021). "Yeast- and antibody-based tools for studying tryptophan C-mannosylation". Nature Chemical Biology. 17 (4): 428–437. doi:10.1038/s41589-020-00727-w. PMID   33542533. S2CID   231811815.
  14. 1 2 "PSORT II Prediction". PSORT. Retrieved 2 May 2017.
  15. ↑ Toldo L. "Isoelectric Point Service". Archived from the original on 2008-10-26.
  16. ↑ "AASTATS: Statistics Based on Amino Acid Abundance, including weight and specific volume".[ permanent dead link ]
  17. 1 2 "SAPS: Statistical Analysis of PS".[ permanent dead link ]
  18. ↑ "SUMOplot".
  19. 1 2 "I-TASSER server for protein structure and function prediction". zhanglab.ccmb.med.umich.edu. Retrieved 2 May 2017.
  20. ↑ "DiANNA". clavius.bc.edu. Archived from the original on 24 July 2022. Retrieved 2 May 2017.
  21. ↑ Remmert M. "Bioinformatics Toolkit". toolkit.tuebingen.mpg.de. Retrieved 2 May 2017.
  22. 1 2 3 "EST Profile - Hs.144725". www.ncbi.nlm.nih.gov. Schuler Group. Retrieved 2 May 2017.
  23. ↑ "GDS1085 / 5768". www.ncbi.nlm.nih.gov. Retrieved 2 May 2017.
  24. 1 2 "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2 May 2017.
  25. 1 2 3 "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2 May 2017.
  26. ↑ Ercan B, Naito T, Hong D, Koh Z, Dharmawan D, Saheki Y (19 February 2021). "Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b". The EMBO Journal. 40 (6): e106524. doi:10.15252/embj.2020106524. PMC   7957428 . PMID   33604931.
  27. ↑ Bandara S, Ramkumar S, Imanishi S, Thomas LD, Sawant OB, Imanishi Y, et al. (12 April 2022). "Aster proteins mediate carotenoid transport in mammalian cells". Proc Natl Acad Sci USA. 119 (15): e2200068119. Bibcode:2022PNAS..11900068B. doi: 10.1073/pnas.2200068119 . PMC   9169810 . PMID   35394870.
  28. 1 2 "STRING: functional protein association networks". string-db.org. Retrieved 2 May 2017.
  29. 1 2 Mike Tyers Lab. "GRAMD1B (UNQ3032/PRO9834) Result Summary | BioGRID". thebiogrid.org. Retrieved 2 May 2017.
  30. ↑ "OMIM Entry: 612559 - Leukemia, chronic lymphocytic, susceptibility to, 5". Online Mendelian Inheritance in Man (OMIM). Retrieved 2 May 2017.
  31. ↑ Lan Q, Au WY, Chanock S, Tse J, Wong KF, Shen M, et al. (December 2010). "Genetic susceptibility for chronic lymphocytic leukemia among Chinese in Hong Kong". European Journal of Haematology. 85 (6): 492–5. doi:10.1111/j.1600-0609.2010.01518.x. PMC   2980583 . PMID   20731705.
  32. ↑ Slager SL, Goldin LR, Strom SS, Lanasa MC, Spector LG, Rassenti L, et al. (April 2010). "Genetic susceptibility variants for chronic lymphocytic leukemia". Cancer Epidemiology, Biomarkers & Prevention. 19 (4): 1098–102. doi:10.1158/1055-9965.EPI-09-1217. PMC   2852480 . PMID   20332261.
  33. ↑ Takeshima H, Ikegami D, Wakabayashi M, Niwa T, Kim YJ, Ushijima T (December 2012). "Induction of aberrant trimethylation of histone H3 lysine 27 by inflammation in mouse colonic epithelial cells". Carcinogenesis. 33 (12): 2384–90. doi: 10.1093/carcin/bgs294 . PMID   22976929.
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