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Gram domain containing 1b

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GRAMD1B
Identifiers
AliasesGRAMD1B, GRAM domain containing 1B, LINC01059, Aster-B
External IDsMGI: 1925037; HomoloGene: 18223; GeneCards: GRAMD1B; OMA:GRAMD1B - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001286563
NM_001286564
NM_020716
NM_001330396

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

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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

mRNA

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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]

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

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

GRAMD1B protein structure

Domains

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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

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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 Repeats Length (aa) Location Similarity Score
1 3 18 Within first 100 amino acids 83.44
2 2 21 GRAM domain 77.22
3 2 22 VASt domain 67.94

Molecular weight and isoelectric point are conserved in orthologs.

Region Amino Acids[5] Isoelectric point[15] Molecular Weight (kdal)[16]
Human GRAMD1B 745 pH of 6.02 86.5
GRAM domain 94 pH of 8.27 11.3
VASt domain 144 pH of 9.41 17.3
Transmembrane region 21 pH of 5.18 2.3

Structure

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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]

Subcellular location

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

Expression

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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

Homology

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Orthologs

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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 species Common Name Accession Number Date of Divergence (MYA)[24] Identity[25]
Homo sapiens Human NP_001273492.1 0 100.00%
Aotus nancymaae Nancy Ma's Night Monkey XP_012325676.1 3.2 99.00%
Papio anubis Olive Baboon XP_017804515.1 29.44 97.00%
Castor canadensis Beaver XP_020037170.1 90 98.00%
Octodon degus Dengu XP_004636450.1 90 97.00%
Pantholops hodgsonii Tibetan Antelope XP_005958036.1 96 99.00%
Bos mutus Domestic Yak XP_005896826.1 96 98.00%
Tursiops truncatus Dolphin XP_019797543 96 83.00%
Elephantulus edwardii Cape Elephant Shrew XP_006895663.1 105 98.00%
Gallus gallus Chicken XP_015153638.1 312 93.00%
Calypte anna Anna's Humming Bird XP_008490701.1 312 91.00%
Pygoscelis adeliae Adelie Penguin XP_009331694.1 312 91.00%
Coturnix japonica Japanese Quail XP_015739426.1 312 90.00%
Anolis carolinensis Carolina Anole XP_008111963.1 312 87.00%
Danio rerio Zebra Fish XP_009303888.1 435 73.00%
Callorhinchus milii Australian Ghost Shark XP_007894251.1 473 77.00%
Branchiostoma belcheri Lancelet XP_019624725.1 684 40.00%
Octopus bimaculoides California Two-Spot Octopus XP_014769036.1 797 40.00%
Lingula anatina Brachiopod XP_013415578 797 38.00%
Zootermopsis nevadensis Termite KDR17240.1 797 37.00%
Trachymyrmex cornetzi Ant XP_018362289.1 797 34.00%

Paralogs

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

Paralog Sequence Length Sequence Identity[25] Date of Divergence (MYA)[24]
GRAMD1A 724 aa 46.60% 421.0
GRAMD1C 662 aa 37.90% 934.7
GRAMD2B/GRAMD3 491 aa 18.50% 1625.6
GRAMD2A 353 aa 16.70% 1724.2

Phylogeny

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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

Function

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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

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

Protein Interaction identified via[28][29] Function Location
COPA Experimental Binds dilysine motifs. Required for budding from the Golgi and retrograde Golgi to ER transport systolic
SPICE1 Data Mining Spindle and centriole associated. Regulates centriole duplication, proper bipolar spindle formation and chromosome congregation in mitosis nuclear
GTPBP8 Data Mining GTP binding protein unconfirmed
Ywhae Co-sedimentation Adapter protein associated with regulating nuclear transport to the cytoplasm nuclear

Clinical significance

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000023171Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040111Ensembl, 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. ^ a b c d "Entrez Gene: GRAM domain containing 1B". Retrieved 2017-02-19.
  6. ^ "UniProtKB - Q3KR37 (ASTRB_HUMAN)". Retrieved March 6, 2020.
  7. ^ a b c d e f g h i j k 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. ^ a b c d e f g h 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. ^ a b "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. ^ a b "SAPS: Statistical Analysis of PS".[permanent dead link]
  18. ^ "SUMOplot".
  19. ^ a b "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. ^ a b c "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. ^ a b "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2 May 2017.
  25. ^ a b c "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. ^ a b "STRING: functional protein association networks". string-db.org. Retrieved 2 May 2017.
  29. ^ a b 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.