Erkan Karakas, Ph.D.

Assistant Professor

erkan.karakas@vanderbilt.edu
Faculty Appointments
Assistant Professor of Molecular Physiology & Biophysics
Education
Ph.D., Molecular and Cellular Biology, Stony Brook University, Stony Brook, New YorkB.S., Molecular Biology and Genetics, Middle East Technical University , Ankara, Turkey
Office Address
735B Light Hall, 2215 Garland Avenue
Nashville, TN 37232
Research Description
Structural Biology of Calcium Signaling and Transport through Biological Membranes

Calcium ions (Ca2+) act as universal messengers required to regulate diverse physiological processes including fertilization, muscle contraction, apoptosis, secretion, and synaptic plasticity. Upon external stimuli, Ca2+-permeable ion channels, which are essential components of the calcium signaling toolkit, mediate the rapid transfer of Ca2+ from the extracellular space or intracellular Ca2+ stores (mainly the endoplasmic reticulum (ER) and mitochondria) to the cytoplasm generating local and global Ca2+ signals. Tight regulation of ion channel activity is critical for proper calcium signaling and aberrant channel activity is associated with many diseases and disorders.

Our major goal is understanding the molecular mechanism and regulation of Ca2+ signaling at the endoplasmic reticulum (ER)-mitochondria contact sites, where ER and mitochondria are linked through proteinaceous tethers located at the specialized ER subdomains named as mitochondria-associated membranes (MAMs) and outer membrane of mitochondria. At these sites, inositol 1,4,5-triphosphate receptors (IP3Rs) release Ca2+ from the ER, creating local hot spots necessary for Ca2+ uptake by mitochondrial calcium uniporter (MCU) in the inner mitochondrial membrane. Sustained Ca2+ transfer to mitochondria is necessary to maintain ATP generation, whereas excessive or reduced calcium transfer leads to initiation of apoptotic cell death or autophagy, respectively. Consequently, Ca2+ signaling at ER-mitochondria interface plays an essential role in cell fate decisions and could be an invaluable target when the cell fate decision machinery is compromised, as observed in cancer (evasion of apoptosis) and neurodegenerative diseases (excessive apoptosis).

Our overall approach is structural characterization of the target proteins using X-ray crystallography and electron cryo-microscopy (cryo-EM) followed by validation of the structural information and the structure-derived hypotheses. We use a repertoire of biophysical and biochemical methods such as analytical ultracentrifugation (AUC), multiangle light scattering (MALS), Isothermal titration calorimetry (ITC), surface plasmon resonance (SPR) and crosslinking to deduce the molecular mechanism of gating, oligomeric assembly, stoichiometry, protein-protein and protein-ligand interactions.
Research Keywords
Structural Biology, X-ray crystallography, cryo-EM, membrane proteins, ion channel, calcium signaling
Publications
Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H. Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain. Neuron [print-electronic]. 2016 Nov 11/21/2016; PMID: 27916457, PII: S0896-6273(16)30844-3, DOI: 10.1016/j.neuron.2016.11.006, ISSN: 1097-4199.

Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R, Grigorieff N, Furukawa H. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature. 2016 Jun 6/2/2016; 534(7605): 63-8. PMID: 27135925, PMCID: PMC5136294, PII: nature17679, DOI: 10.1038/nature17679, ISSN: 1476-4687.

Karakas E, Regan MC, Furukawa H. Emerging structural insights into the function of ionotropic glutamate receptors. Trends Biochem. Sci [print-electronic]. 2015 Jun; 40(6): 328-37. PMID: 25941168, PMCID: PMC4464829, PII: S0968-0004(15)00078-X, DOI: 10.1016/j.tibs.2015.04.002, ISSN: 0968-0004.

Khatri A, Burger PB, Swanger SA, Hansen KB, Zimmerman S, Karakas E, Liotta DC, Furukawa H, Snyder JP, Traynelis SF. Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator. Mol. Pharmacol [print-electronic]. 2014 Nov; 86(5): 548-60. PMID: 25205677, PMCID: PMC4201136, PII: mol.114.094516, DOI: 10.1124/mol.114.094516, ISSN: 1521-0111.

Karakas E, Furukawa H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science. 2014 May 5/30/2014; 344(6187): 992-7. PMID: 24876489, PMCID: PMC4113085, PII: 344/6187/992, DOI: 10.1126/science.1251915, ISSN: 1095-9203.

Burger PB, Yuan H, Karakas E, Geballe M, Furukawa H, Liotta DC, Snyder JP, Traynelis SF. Mapping the binding of GluN2B-selective N-methyl-D-aspartate receptor negative allosteric modulators. Mol. Pharmacol [print-electronic]. 2012 Aug; 82(2): 344-59. PMID: 22596351, PMCID: PMC3400845, PII: mol.112.078568, DOI: 10.1124/mol.112.078568, ISSN: 1521-0111.

Karakas E, Simorowski N, Furukawa H. Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature. 2011 Jun 6/15/2011; 475(7355): 249-53. PMID: 21677647, PMCID: PMC3171209, PII: nature10180, DOI: 10.1038/nature10180, ISSN: 1476-4687.

Karakas E, Simorowski N, Furukawa H. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J. 2009 Dec 12/16/2009; 28(24): 3910-20. PMID: 19910922, PMCID: PMC2797058, PII: emboj2009338, DOI: 10.1038/emboj.2009.338, ISSN: 1460-2075.

Karakas E, Truglio JJ, Croteau D, Rhau B, Wang L, Van Houten B, Kisker C. Structure of the C-terminal half of UvrC reveals an RNase H endonuclease domain with an Argonaute-like catalytic triad. EMBO J. 2007 Jan 1/24/2007; 26(2): 613-22. PMID: 17245438, PMCID: PMC1783470, PII: 7601497, DOI: 10.1038/sj.emboj.7601497, ISSN: 0261-4189.

Truglio JJ, Karakas E, Rhau B, Wang H, DellaVecchia MJ, Van Houten B, Kisker C. Structural basis for DNA recognition and processing by UvrB. Nat. Struct. Mol. Biol [print-electronic]. 2006 Apr; 13(4): 360-4. PMID: 16532007, PII: nsmb1072, DOI: 10.1038/nsmb1072, ISSN: 1545-9993.

Karakas E, Kisker C. Structural analysis of missense mutations causing isolated sulfite oxidase deficiency. Dalton Trans [print-electronic]. 2005 Nov 11/7/2005; (21): 3459-63. PMID: 16234925, DOI: 10.1039/b505789m, ISSN: 1477-9226.

Karakas E, Wilson HL, Graf TN, Xiang S, Jaramillo-Busquets S, Rajagopalan KV, Kisker C. Structural insights into sulfite oxidase deficiency. J. Biol. Chem [print-electronic]. 2005 Sep 9/30/2005; 280(39): 33506-15. PMID: 16048997, PII: M505035200, DOI: 10.1074/jbc.M505035200, ISSN: 0021-9258.

Truglio JJ, Rhau B, Croteau DL, Wang L, Skorvaga M, Karakas E, DellaVecchia MJ, Wang H, Van Houten B, Kisker C. Structural insights into the first incision reaction during nucleotide excision repair. EMBO J [print-electronic]. 2005 Mar 3/9/2005; 24(5): 885-94. PMID: 15692561, PMCID: PMC554121, PII: 7600568, DOI: 10.1038/sj.emboj.7600568, ISSN: 0261-4189.

Available Postdoctoral Position Details
Posted: 6/6/2017

A postdoctoral position is available in the Karakas lab at Vanderbilt University School of Medicine. Our group is interested in understanding the molecular mechanism of intracellular ion channels involved in calcium signaling using structural biology approaches. The applicants should have experience in basic molecular biology and protein expression/purification. Experience in X-ray crystallography or electron cryo-microscopy would be a plus, but not required.

To apply, please send a cover letter explaining your research interests and goals, a CV and contact information for 2-3 references to Erkan Karakas at erkan.karakas@vanderbilt.edu.