adhesion-type G protein coupled receptors, GAIN domains, brain functions and diseases
University of Chicago, Assistant Professor, 2013-
Stanford University, Postdoctoral fellow, 2006-2013
University of Texas Southwestern Medical Center at Dallas, Ph.D. in Molecular Biophysics, 2000-2006
Bilkent University, B.Sc. in Molecular Biology and Genetics, 1995-1999
Life Sciences Research Foundation (LSRF), Post-doctoral Fellowship (sponsored by HHMI), 2007-2010
Chancellor’s Distinguished Fellowship, University of California, Riverside, Graduate Student Fellowship, 1999-2000
St. Mary’s School of Medicine, UK, Summer Undergraduate Research Fellow, Full Scholarship, 1998 and 1999
B.S., Bilkent University, Full Scholarship, 1995-1999
TUBITAK, Young Scientist Scholarship, 1995-1996
Structure and Function of Membrane Proteins (together with Eduardo Perozo)
The G-protein coupled receptor (GPCR) superfamily is the largest group of membrane proteins and the most commonly targeted group of molecules for the treatment of human diseases. Adhesion-type GPCRs are a newly discovered GPCR family with emerging roles in multiple brain functions and disorders such as brain development, synapse maturation/elimination, bilateral frontoparietal polymicrogyria (BFPP, a neurodevelopmental disorder), attention-deficit hyperactivity disorder, and cancers of the brain. The goal of our laboratory is to understand the mechanism by which adhesion GPCRs function in the brain, and to decipher the role of the newly discovered GPCR Autoproteolysis Inducing (GAIN) domain in their function. We aim to identify ligands for adhesion GPCRs and to reveal the molecular mechanisms by which adhesion GPCRs recognize their ligands through their GAIN domains and transmembrane helices. We also aim to shed light on how the extracellular GAIN domain and the membrane-embedded transmembrane helices act together to regulate receptor activity. We explore these questions from a biochemical/biophysical point of view through protein biochemistry, x-ray crystallography, and biophysical techniques. We complement our molecular studies with functional studies to understand the structure/function relationship and put our findings at the molecular level in the context of the physiological receptor activity. Our results will have an enormous impact scientifically by elucidating how cellular adhesion couples to intracellular signaling in multicellular organisms, a key phenomenon that is disrupted in many human diseases, and, translationally, through targeted drug design to treat brain diseases caused by malfunctioning adhesion GPCRs.
Prömel S, Langenhan T, Araç D. Matching structure with function: the GAIN domain of Adhesion-GPCR and PKD1-like proteins. Trends Pharmacol Sci. 2013 Jul 10. PMID: 23850273.
Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH, Monk KR, Petrenko A, Piao X, Prömel S, Schiöth HB, Schwartz TW, Stacey M, Ushkaryov YA, Wobus M, Wolfrum U, Xu L, Langenhan T. Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 2012 Dec; 1276:1-25. PMID: 23215895.
Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 2012 Mar 21; 31(6):1364-78. PMID: 22333914.
Zhang C, Atasoy D, Araç D, Yang X, Fucillo MV, Robison AJ, Ko J, Brunger AT, Südhof TC. Neurexins physically and functionally interact with GABA(A) receptors. Neuron. 2010 May 13; 66(3):403-16. PMID: 20471353.
Ko J, Zhang C, Arac D, Boucard AA, Brunger AT, Südhof TC. Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation. EMBO J. 2009 Oct 21; 28(20):3244-55. PMID: 19730411.
Zuniga JE, Schmidt JJ, Fenn T, Burnett JC, Araç D, Gussio R, Stafford RG, Badie SS, Bavari S, Brunger AT. A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate. Structure. 2008 Oct 8; 16(10):1588-97. PMID: 18940613.
Araç D, Boucard AA, Özkan E, Strop P, Newell E, Südhof TC, Brunger AT. Structures of neuroligin-1 and the neuroligin-1/neurexin-1 beta complex reveal specific protein-protein and protein-Ca2+ interactions. Neuron. 2007 Dec 20; 56(6):992-1003. PMID: 18093522.
Dai H, Shen N, Araç D, Rizo J. A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. J Mol Biol. 2007 Mar 30; 367(3):848-63. PMID: 17320903.
Rizo J, Chen X, Araç D. Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release. Trends Cell Biol. 2006 Jul; 16(7):339-50. PMID: 16698267.
Li L, Shin OH, Rhee JS, Araç D, Rah JC, Rizo J, Südhof T, Rosenmund C. Phosphatidylinositol phosphates as co-activators of Ca2+ binding to C2 domains of synaptotagmin 1. J Biol Chem. 2006 Jun 9; 281(23):15845-52. PMID: 16595652.
Chen X, Araç D, Wang TM, Gilpin CJ, Zimmerberg J, Rizo J. SNARE-mediated lipid mixing depends on the physical state of the vesicles. Biophys J. 2006 Mar 15; 90(6):2062-74. PMID: 16361343.
Araç D, Chen X, Khant HA, Ubach J, Ludtke SJ, Kikkawa M, Johnson AE, Chiu W, Südhof TC, Rizo J. Close membrane-membrane proximity induced by Ca(2+)-dependent multivalent binding of synaptotagmin-1 to phospholipids. Nat Struct Mol Biol. 2006 Mar; 13(3):209-17. PMID: 16491093.
Ferguson AD, Labunskyy VM, Fomenko DE, Araç D, Chelliah Y, Amezcua CA, Rizo J, Gladyshev VN, Deisenhofer J. NMR structures of the selenoproteins Sep15 and SelM reveal redox activity of a new thioredoxin-like family. J Biol Chem. 2006 Feb 10; 281(6):3536-43. PMID: 16319061.
Araç D, Dulubova I, Pei J, Huryeva I, Grishin NV, Rizo J. Three-dimensional structure of the rSly1 N-terminal domain reveals a conformational change induced by binding to syntaxin 5. J Mol Biol. 2005 Feb 18; 346(2):589-601. PMID: 15670607.
Jarousse N, Wilson JD, Arac D, Rizo J, Kelly RB. Endocytosis of synaptotagmin 1 is mediated by a novel, tryptophan-containing motif. Traffic. 2003 Jul; 4(7):468-78. PMID: 12795692.
Araç D, Murphy T, Rizo J. Facile detection of protein-protein interactions by one-dimensional NMR spectroscopy. Biochemistry. 2003 Mar 18; 42(10):2774-80. PMID: 12627942.
Dulubova I, Yamaguchi T, Arac D, Li H, Huryeva I, Min SW, Rizo J, Sudhof TC. Convergence and divergence in the mechanism of SNARE binding by Sec1/Munc18-like proteins. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):32-7. PMID: 12506202.
Kulik V, Weyand M, Seidel R, Niks D, Arac D, Dunn MF, Schlichting I. On the role of alphaThr183 in the allosteric regulation and catalytic mechanism of tryptophan synthase. J Mol Biol. 2002 Dec 6; 324(4):677-90. PMID: 12460570.
Antonin W, Dulubova I, Arac D, Pabst S, Plitzner J, Rizo J, Jahn R. The N-terminal domains of syntaxin 7 and vti1b form three-helix bundles that differ in their ability to regulate SNARE complex assembly. J Biol Chem. 2002 Sep 27; 277(39):36449-56. PMID: 12114520.
Hafezparast M, Ball S, Nicholson SJ, Witherden A, Arac D, Broadway N, Saggerson D, Cooper E, Naase M, Gokhale S, Quant P, Lascelles C, Nickols C, Baker CS, Peters J, Martin JE, Fisher EM. A new mouse mutant, skijumper. Mamm Genome. 2002 Jul; 13(7):359-364. PMID: 12152619.
Chen X, Tomchick DR, Kovrigin E, Araç D, Machius M, Südhof TC, Rizo J. Three-dimensional structure of the complexin/SNARE complex. Neuron. 2002 Jan 31; 33(3):397-409. PMID: 11832227.
Witherden AS, Hafezparast M, Nicholson SJ, Ahmad-Annuar A, Bermingham N, Arac D, Rankin J, Iravani M, Ball S, Peters J, Martin JE, Huntley D, Hummerich H, Sergot M, Fisher EM. An integrated genetic, radiation hybrid, physical and transcription map of a region of distal mouse chromosome 12, including an imprinted locus and the 'Legs at odd angles' (Loa) mutation. Gene. 2002 Jan 23; 283(1-2):71-82. PMID: 11867214.
Fernandez I, Araç D, Ubach J, Gerber SH, Shin O, Gao Y, Anderson RG, Südhof TC, Rizo J. Three-dimensional structure of the synaptotagmin 1 C2B-domain: synaptotagmin 1 as a phospholipid binding machine. Neuron. 2001 Dec 20; 32(6):1057-69. PMID: 11754837.
Ubach J, Lao Y, Fernandez I, Arac D, Südhof TC, Rizo J. The C2B domain of synaptotagmin I is a Ca2+-binding module. Biochemistry. 2001 May 22; 40(20):5854-60. PMID: 11352720.