Gram domain containing 1b

GRAM domain containing 1B, also known as GRAMD1B, Aster-B and KIAA1201, is a protein that is encoded by the GRAMD1B gene.[5][6] 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.[7]

GRAMD1B
Identifiers
Aliases	GRAMD1B, GRAM domain containing 1B, LINC01059
External IDs	MGI: 1925037 HomoloGene: 18223 GeneCards: GRAMD1B
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q24.1 Start 123,358,428 bp[1] End 123,627,774 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 A5.1 Start 40,293,233 bp[2] End 40,531,383 bp[2]
Gene ontology Molecular function • phosphatidylserine binding • lipid binding • cholesterol binding • phosphatidic acid binding • GO:0017127 cholesterol transfer activity Cellular component • membrane • integral component of membrane • endoplasmic reticulum • endoplasmic reticulum membrane • cell membrane • endoplasmic reticulum-plasma membrane contact site Biological process • lipid transport • cholesterol transport • cholesterol homeostasis • cellular response to cholesterol • intermembrane sterol transfer Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	57476	235283
Ensembl	ENSG00000023171	ENSMUSG00000040111
UniProt	Q3KR37	Q80TI0
RefSeq (mRNA)	NM_001286563 NM_001286564 NM_020716 NM_001330396	NM_172768 NM_001357617 NM_001357618 NM_001357619 NM_001357620 NM_001357621 NM_001357622 NM_001357623
RefSeq (protein)	NP_001273492 NP_001273493 NP_001317325 NP_065767 NP_001341766 NP_001354347 NP_001354348 NP_001354349 NP_001354350	NP_766356 NP_001344546 NP_001344547 NP_001344548 NP_001344549 NP_001344550 NP_001344551 NP_001344552
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

Gene

GRAMD1B, also known as KIAA1201, is located in the human genome at 11q24.1.[8] 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

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.

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.

GRAMD1B protein structure

Domains

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.[9] 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.[10]

Composition Features

There are two negative charge clusters, located from amino acids 232-267 and 348-377.[11] 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.[11]

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[12]	Molecular Weight (kdal)[13]
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

The mature protein contains two nuclear localization signals, pat4 and pat7.[14] There are four dileucine motifs, three located within or close to the GRAM domain.[14] A leucine zipper pattern extends through a majority the transmembrane region.[14] A SUMOylation site is located directly after the VASt domain.[15] The proteins secondary structure consists of alpha-helices, beta-strands and coils.[16] 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.[17]

Predicted alpha-helix structure of GRAMD1B transmembrane region.[18]

Predicted 3D structure of GRAMD1B,[16]

Subcellular location

GRAMD1B is predicted to localize in the nucleus and contains a transmembrane domain, most likely placing it in the membrane of the nucleus.[11]

Expression

GRAMD1B is expressed in a variety of tissues. It is most highly expressed in the gonadal tissue, adrenal gland, brain and placenta.[19] 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[20]

GRAMD1B expression in a variety of tissues.[19]

[19] 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. It is not present in bacteria, archaea or fungi.[7]

Genus species	Common Name	Accession Number	Date of Divergence (MYA)[21]	Identity[7]
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

There are four paralogs of GRAMD1B.[7] The most closely related is GRAMD1A while the most distant ortholog is GRAMD2A/GRAMD2.

Paralog	Sequence Length	Sequence Identity[7]	Date of Divergence (MYA)[21]
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

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

Currently, the function of GRAMD1B has not been characterized.

Protein interactions

Several different proteins have been experimentally confirmed or predicted to interact with GRAMD1B.[22][23]

Protein	Interaction identified via[22][23]	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

A study tagging SNPs from chronic lymphocytic leukemia found GRAMD1B to be the second strongest risk allele region.[24] This association is supported through a number of studies[25][26] The aberrant tri-methylation of histone H3 lysine 27 induces inflammation and has been shown to increase GRAMD1B levels in colon tumors.[27]

References

1. GRCh38: Ensembl release 89: ENSG00000023171 - Ensembl, May 2017
2. 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. "Entrez Gene: GRAM domain containing 1B". Retrieved 2017-02-19.
6. "UniProtKB - Q3KR37 (ASTRB_HUMAN)". Retrieved March 6, 2020.
7. "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2 May 2017.
8. "GRAMD1B Gene - GeneCards | GRM1B Protein | GRM1B Antibody". GeneCards Human Gene. Retrieved 2 May 2017.
9. "GRAM Protein Domain".
10. "PROSITE". prosite.expasy.org. Retrieved 2 May 2017.
11. "PSORT II Prediction". PSORT. Retrieved 2 May 2017.
12. Toldo L. "Isoelectric Point Service". Archived from the original on 2008-10-26.
13. "AASTATS: Statistics Based on Amino Acid Abundance, including weight and specific volume".
14. "SAPS: Statistical Analysis of PS".
15. "SUMOplot".
16. "I-TASSER server for protein structure and function prediction". zhanglab.ccmb.med.umich.edu. Retrieved 2 May 2017.
17. "DiANNA". clavius.bc.edu. Retrieved 2 May 2017.
18. Remmert M. "Bioinformatics Toolkit". toolkit.tuebingen.mpg.de. Retrieved 2 May 2017.
19. "EST Profile - Hs.144725". www.ncbi.nlm.nih.gov. Schuler Group. Retrieved 2 May 2017.
20. "GDS1085 / 5768". www.ncbi.nlm.nih.gov. Retrieved 2 May 2017.
21. "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2 May 2017.
22. "STRING: functional protein association networks". string-db.org. Retrieved 2 May 2017.
23. Lab, Mike Tyers. "GRAMD1B (UNQ3032/PRO9834) Result Summary | BioGRID". thebiogrid.org. Retrieved 2 May 2017.
24. "OMIM Entry: 612559 - Leukemia, chronic lymphocytic, susceptibility to, 5". Online Mendelian Inheritance in Man (OMIM). Retrieved 2 May 2017.
25. Lan Q, Au WY, Chanock S, Tse J, Wong KF, Shen M, Siu LP, Yuenger J, Yeager M, Hosgood HD, Purdue MP, Liang R, Rothman N (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.
26. Slager SL, Goldin LR, Strom SS, Lanasa MC, Spector LG, Rassenti L, Leis JF, Camp NJ, Kay NE, Vachon CM, Glenn M, Weinberg JB, Rabe KG, Cunningham JM, Achenbach SJ, Hanson CA, Marti GE, Call TG, Caporaso NE, Cerhan JR (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.
27. 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.