Nashville, TN 37212
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.
Takahashi H, Yamada T, Denton JS, Strange K, Karakas E. Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly. Elife. 2023 Mar 3/10/2023; 12: PMID: 36897307, PMCID: PMC10049205, PII: 82431, DOI: 10.7554/eLife.82431, ISSN: 2050-084X.
Ravera S, Nicola JP, Salazar-De Simone G, Sigworth FJ, Karakas E, Amzel LM, Bianchet MA, Carrasco N. Structural insights into the mechanism of the sodium/iodide symporter. Nature [print-electronic]. 2022 Dec; 612(7941): 795-801. PMID: 36517601, PII: 10.1038/s41586-022-05530-2, DOI: 10.1038/s41586-022-05530-2, ISSN: 1476-4687.
Porta JC, Han B, Gulsevin A, Chung JM, Peskova Y, Connolly S, Mchaourab HS, Meiler J, Karakas E, Kenworthy AK, Ohi MD. Molecular architecture of the human caveolin-1 complex. Sci Adv [print-electronic]. 2022 May 5/13/2022; 8(19): eabn7232. PMID: 35544577, PMCID: PMC9094659, DOI: 10.1126/sciadv.abn7232, ISSN: 2375-2548.
Schmitz EA, Takahashi H, Karakas E. Structural basis for activation and gating of IP3 receptors. Nat Commun. 2022 Mar 3/17/2022; 13(1): 1408. PMID: 35301323, PMCID: PMC8930994, PII: 10.1038/s41467-022-29073-2, DOI: 10.1038/s41467-022-29073-2, ISSN: 2041-1723.
Han B, Porta JC, Hanks JL, Peskova Y, Binshtein E, Dryden K, Claxton DP, Mchaourab HS, Karakas E, Ohi MD, Kenworthy AK. Structure and assembly of CAV1 8S complexes revealed by single particle electron microscopy. Sci Adv [electronic-print]. 2020 Dec; 6(49): PMID: 33268374, PII: 6/49/eabc6185, DOI: 10.1126/sciadv.abc6185, ISSN: 2375-2548.
Azumaya CM, Linton EA, Risener CJ, Nakagawa T, Karakas E. Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist. J. Biol. Chem [print-electronic]. 2020 Feb 2/7/2020; 295(6): 1743-53. PMID: 31915246, PII: RA119.011570, DOI: 10.1074/jbc.RA119.011570, ISSN: 1083-351X.
Regan MC, Grant T, McDaniel MJ, Karakas E, Zhang J, Traynelis SF, Grigorieff N, Furukawa H. Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors. Neuron [print-electronic]. 2018 May 5/2/2018; 98(3): 521-529.e3. PMID: 29656875, PMCID: PMC5963293, PII: S0896-6273(18)30240-X, DOI: 10.1016/j.neuron.2018.03.034, ISSN: 1097-4199.
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.
The Karakas Lab at Vanderbilt University School of Medicine, located in Nashville, TN, is seeking a highly motivated individual to fill an NIH-funded postdoctoral position. Our research group is dedicated to unraveling the molecular mechanisms of ion channels using state-of-the-art structural biology approaches. The laboratory, situated within the Department of Molecular Physiology and Biophysics, offers access to cutting-edge cores specializing in crystallography, cryo-electron microscopy (cryo-EM), mass spectrometry, and a range of advanced biophysical instrumentation.
We invite you to explore our recent research publications that demonstrate our significant contributions to understanding diverse ion channels and their underlying structural basis:
Structural basis for activation and gating of IP3 receptors (https://www.nature.com/articles/s41467-022-29073-2)
Cryo-EM structures of an LRRC8 chimera with native functional properties reveal heptameric assembly (https://elifesciences.org/articles/82431)
As a Postdoctoral Researcher in our lab, you will work closely with Dr. Karakas, utilizing cutting-edge technologies such as X-ray crystallography, cryo-EM, and various biophysical techniques. You will have the freedom to design and conduct experiments, analyze data, and contribute to the development of novel methodologies. Candidates should have a Ph.D. in biochemistry, biophysics, or related fields. While prior experience in X-ray crystallography, cryo-EM, or electrophysiology would be advantageous, it is not required. We welcome applicants with diverse backgrounds and a strong interest in applying structural biology techniques to study ion channels.
To apply for this position, please submit the following documents via e-mail to Erkan Karakas at erkan.karakas@vanderbilt.edu:
• Cover Letter: Please provide a cover letter that outlines your research interests, goals, and how your background aligns with our research focus.
• CV: Attach a current curriculum vitae highlighting your educational background, research experience, and publications.
• References: Include the contact information (2-3 references) who can provide insight into your qualifications and potential as a postdoctoral researcher.
We encourage interested candidates to apply as soon as possible. The position will remain open until filled.
For any additional inquiries or further information, please do not hesitate to contact Erkan Karakas at erkan.karakas@vanderbilt.edu or by phone at (615) 343-4494.