cd15988

brain-specific angiogenesis inhibitor 2, a group VII adhesion GPCR, member of the class B2 family of seven-transmembrane G protein-coupled receptors

CDD entry
Member databaseCDD
CDD typedomain
Short name7tmB2_BAI2
Set7tm_GPCRs

Description

Brain-specific angiogenesis inhibitors (BAI1-3) constitute the group VII of cell-adhesion receptors that have been implicated in vascularization of glioblastomas. They belong to the B2 subfamily of class B GPCRs, are predominantly expressed in the brain, and are only present in vertebrates. Three BAIs, like all adhesion receptors, are characterized by the presence of large N-terminal extracellular domains containing multiple adhesion motifs, which play critical roles in cell-cell adhesion and cell-matrix interactions, that are coupled to a class B seven-transmembrane domain. For example, BAI1 N-terminus contain an integrin-binding RGD (Arg-Gly-Asp) motif in addition to five thrombospondin type 1 repeats (TSRs), which are known to regulate the anti-angiogenic activity of thrombospondin-1, whereas BAI2 and BAI3 have four TSRs, but do not possess RGD motifs. The TSRs are functionally involved in cell attachment, activation of latent TGF-beta, inhibition of angiogenesis and endothelial cell migration. The TSRs of BAI1 mediates direct binding to phosphatidylserine, which enables both recognition and internalization of apoptotic cells by phagocytes. Thus, BAI1 functions as a phosphatidylserine receptor that forms a trimeric complex with ELMO and Dock180, leading to activation of Rac-GTPase which promotes the binding and phagocytosis of apoptotic cells. BAI3 can also interact with the ELMO-Dock180 complex to activate the Rac pathway and can also bind to secreted C1ql proteins of the C1Q complement family via its N-terminal TSRs. BAI3 and its ligands C1QL1 are highly expressed during synaptogenesis and are involved in synapse specificity. Moreover, BAI2 acts as a transcription repressor to regulate vascular endothelial growth factor (VEGF) expression through interaction with GA-binding protein gamma (GABP). The N-terminal extracellular domains of all three BAIs also contain an evolutionarily conserved GPCR-autoproteolysis inducing (GAIN) domain, which undergoes autoproteolytic processing at the GPCR proteolysis site (GPS) motif to generate N- and C-terminal fragments (NTF and CTF), a putative hormone-binding domain (HBD), and multiple N-glycosylation sites. The C-terminus of each BAI subtype ends with a conserved Gln-Thr-Glu-Val (QTEV) motif known to interact with PDZ domain-containing proteins, but only BAI1 possesses a proline-rich region, which may be involved in protein-protein interactions.
[5, 24, 10, 1, 8, 19, 16, 25, 3, 14, 15, 13, 23, 28, 2, 9, 27, 21, 17, 6, 18, 12, 22, 4, 11, 26, 7, 20]

References

1.G protein-coupled receptors: two landmark class B GPCR structures unveiled. Tse MT. Nat Rev Drug Discov 12, 579, (2013). PMID: 23903216

2.G proteins in signal transduction. Birnbaumer L. Annu. Rev. Pharmacol. Toxicol. 30, 675-705, (1990). View articlePMID: 2111655

3.Learning from the past: evolution of GPCR functions. Schoneberg T, Hofreiter M, Schulz A, Rompler H. Trends Pharmacol. Sci. 28, 117-21, (2007). View articlePMID: 17280721

4.The evolution of the GPCR signaling system in eukaryotes: modularity, conservation, and the transition to metazoan multicellularity. de Mendoza A, Sebe-Pedros A, Ruiz-Trillo I. Genome Biol Evol 6, 606-19, (2014). View articlePMID: 24567306

5.Family-B G-protein-coupled receptors. Harmar AJ. Genome Biol. 2, REVIEWS3013, (2001). View articlePMID: 11790261

6.Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Deupi X, Kobilka BK. Physiology (Bethesda) 25, 293-303, (2010). View articlePMID: 20940434

7.The BAI subfamily of adhesion GPCRs: synaptic regulation and beyond. Stephenson JR, Purcell RH, Hall RA. Trends Pharmacol Sci 35, 208-15, (2014). PMID: 24642458

8.The family B1 GPCR: structural aspects and interaction with accessory proteins. Couvineau A, Laburthe M. Curr Drug Targets 13, 103-15, (2012). PMID: 21777182

9.G protein-coupled receptor deorphanizations. Civelli O, Reinscheid RK, Zhang Y, Wang Z, Fredriksson R, Schioth HB. Annu. Rev. Pharmacol. Toxicol. 53, 127-46, (2013). PMID: 23020293

10.A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Nishimori H, Shiratsuchi T, Urano T, Kimura Y, Kiyono K, Tatsumi K, Yoshida S, Ono M, Kuwano M, Nakamura Y, Tokino T. Oncogene 15, 2145-50, (1997). View articlePMID: 9393972

11.The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. Bjarnadottir TK, Fredriksson R, Schioth HB. Cell Mol Life Sci 64, 2104-19, (2007). PMID: 17502995

12.Structure-based drug screening for G-protein-coupled receptors. Shoichet BK, Kobilka BK. Trends Pharmacol. Sci. 33, 268-72, (2012). View articlePMID: 22503476

13.Structure and dynamics of G-protein coupled receptors. Vaidehi N, Bhattacharya S, Larsen AB. Adv Exp Med Biol 796, 37-54, (2014). PMID: 24158800

14.From three-dimensional GPCR structure to rational ligand discovery. Kooistra AJ, Leurs R, de Esch IJ, de Graaf C. Adv. Exp. Med. Biol. 796, 129-57, (2014). View articlePMID: 24158804

15.Structure-function of the G protein-coupled receptor superfamily. Katritch V, Cherezov V, Stevens RC. Annu. Rev. Pharmacol. Toxicol. 53, 531-56, (2013). View articlePMID: 23140243

16.The adhesion GPCRs; gene repertoire, phylogeny and evolution. Schioth HB, Nordstrom KJ, Fredriksson R. Adv Exp Med Biol 706, 1-13, (2010). PMID: 21618822

17.Evolution of GPCR: change and continuity. Strotmann R, Schrock K, Boselt I, Staubert C, Russ A, Schoneberg T. Mol Cell Endocrinol 331, 170-8, (2011). PMID: 20708652

18.Structural insights into G-protein-coupled receptor activation. Weis WI, Kobilka BK. Curr. Opin. Struct. Biol. 18, 734-40, (2008). View articlePMID: 18957321

19.Insights into the structure of class B GPCRs. Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC. Trends Pharmacol Sci 35, 12-22, (2014). PMID: 24359917

20.The Secretin GPCRs descended from the family of Adhesion GPCRs. Nordstrom KJ, Lagerstrom MC, Waller LM, Fredriksson R, Schioth HB. Mol Biol Evol 26, 71-84, (2009). PMID: 18845549

21.G protein-coupled receptors--recent advances. Latek D, Modzelewska A, Trzaskowski B, Palczewski K, Filipek S. Acta Biochim. Pol. 59, 515-29, (2012). PMID: 23251911

22.Adhesion-GPCRs: emerging roles for novel receptors. Yona S, Lin HH, Siu WO, Gordon S, Stacey M. Trends Biochem Sci 33, 491-500, (2008). PMID: 18789697

23.Sticky signaling--adhesion class G protein-coupled receptors take the stage. Langenhan T, Aust G, Hamann J. Sci Signal 6, re3, (2013). PMID: 23695165

24.Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Shiratsuchi T, Nishimori H, Ichise H, Nakamura Y, Tokino T. Cytogenet. Cell Genet. 79, 103-8, (1997). PMID: 9533023

25.Phylogenomic analysis reveals extensive phylogenetic mosaicism in the human GPCR superfamily. Allaby RG, Woodwark M. Evol. Bioinform. Online 3, 357-70, (2007). PMID: 19468313

26.A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. Arac D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Sudhof TC, Brunger AT. EMBO J. 31, 1364-78, (2012). View articlePMID: 22333914

27.International Union of Pharmacology. XLVI. G protein-coupled receptor list. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. Pharmacol. Rev. 57, 279-88, (2005). View articlePMID: 15914470

28.Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. Paavola KJ, Hall RA. Mol Pharmacol 82, 777-83, (2012). PMID: 22821233

External Links
This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice and Terms of Use.