Gram ___domain containing 1a

GRAM ___domain containing 1A also known as Aster-A is a protein that is encoded by the GRAMD1A gene. ^[5][6] It contains a transmembrane region, a GRAM ___domain and a VASt ___domain that can bind cholesterol.^[7][8] 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.^[7]

GRAMD1A
Identifiers
Aliases	GRAMD1A, KIAA1533, GRAM ___domain containing 1A, Aster-A
External IDs	MGI: 105490; HomoloGene: 10843; GeneCards: GRAMD1A; OMA:GRAMD1A - orthologs
Gene ___location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.11 Start 34,994,784 bp[1] End 35,026,471 bp[1]
Gene ___location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7 B1|7 19.3 cM Start 30,829,552 bp[2] End 30,855,321 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in body of pancreas upper lobe of left lung right uterine tube left uterine tube canal of the cervix left ovary right ovary gastric mucosa appendix right lung Top expressed in granulocyte thymus lymph node superior frontal gyrus ganglionic eminence muscle of thigh visual cortex primary visual cortex ventricular zone interventricular septum More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding cholesterol binding cholesterol transfer activity lipid binding Cellular component membrane integral component of membrane intrinsic component of endoplasmic reticulum membrane extrinsic component of cytoplasmic side of plasma membrane organelle membrane contact site endoplasmic reticulum endoplasmic reticulum membrane plasma membrane endoplasmic reticulum-plasma membrane contact site Biological process cholesterol transport cellular response to cholesterol intermembrane sterol transfer lipid transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57655 52857 Ensembl ENSG00000089351 ENSMUSG00000001248 UniProt Q96CP6 Q8VEF1 RefSeq (mRNA) NM_001136199 NM_020895 NM_001320034 NM_001320035 NM_001320036 NM_027898 NM_001360351 RefSeq (protein) NP_001129671 NP_001306963 NP_001306964 NP_001306965 NP_065946 NP_082174 NP_001347280 Location (UCSC) Chr 19: 34.99 – 35.03 Mb Chr 7: 30.83 – 30.86 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The protein is expressed ubiquitously with higher levels in the central nervous system.^[9]

Function

GRAMD1A localizes to the endoplasmic reticulum.^[7] Its GRAM ___domain tethers it to the plasma membrane where it can bind phosphatidylinositol phosphate in areas enriched for it.^[7][10]

When the plasma membrane contains high levels of cholesterol, GRAMD1a like GRAMD1b and GRAMD1c moves to sites of contact between the plasma membrane and the endoplasmic reticulum.^[8] The VASt ___domain of GRAMD1A then binds cholesterol and cholesterol is moved from the plasma membrane to the endoplasmic reticulum.^[8][11] 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][12]

GRAMD1A also is necessary for autophagosome biogenesis.^[11]

References

1. GRCh38: Ensembl release 89: ENSG00000089351 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001248 – 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 1A". Retrieved 2017-09-15.
6. "UniProtKB - Q8VEF1 (ASTRA_MOUSE)". Retrieved March 6, 2020.
7. Besprozvannaya M, Dickson E, Li H, Ginburg KS, Bers DM, Auwerx J, Nunnari J (February 2018). "GRAM ___domain proteins specialize functionally distinct ER-PM contact sites in human cells". eLife. 22 (7): e31019. doi:10.7554/eLife.31019. PMC 5823543. PMID 29469807.
8. Sandhu J, Li S, Fairall L, Pfisterer SG, Gurnett JE, Xiao X, Weston TA, Vashi D, Ferrari A, Orozco JL, Hartman CL, Strugatsky D, Lee SD, He C, Hong C, Jiang H, Bentolila LA, Gatta AT, Levine TP, Ferng A, Lee R, Ford DA, Young SG, Ikonen E, Schwabe JW, Tontonoz P (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. 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.
10. Wu YW, Waldmann H (December 2019). "Toward the role of cholesterol and cholesterol transfer protein in autophagosome biogenesis". Autophagy. 15 (12): 2167–2168. doi:10.1080/15548627.2019.1666595. PMC 6844521. PMID 31512558.
11. Laraia L, Friese A, Corkery DP, Konstantinidis G, Erwin N, Hofer W, Karatas H, Klewer L, Brockmeyer A, Metz M, Schölermann B, Dwivedi M, Li L, Rios-Munoz P, Köhn M, Winter R, Vetter IR, Ziegler S, Janning P, Wu YW, Waldmann H (July 2019). "The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis" (PDF). Nat. Chem. Biol. 15 (7): 710–720. doi:10.1038/s41589-019-0307-5. PMID 31222192. S2CID 195191486.
12. 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.

Further reading