Prof. Dr. Volodymyr Korkhov

Associate Professor
Institute of Molecular Biology and Biophysics, ETH Zurich

Interactions between the cell and its environment, as well as between different cellular compartments, occur at the biological membranes. Extracellular signals are sensed by the receptors at the cell surface. These signals are then transmited across the membrane via multiple biomolecular interactions involving membrane-bound and soluble proteins, resulting in complex biochemical responses inside the cell. The process of signal transduction is critically important for physiology in health and disease. The research in my group is focused on understanding the molecular mechanisms of signal transduction. Using a multidisciplinary approach including methods of membrane protein biochemistry, biophysics and structural biology (including X-ray crystallography and cryo-EM), we aim to understand the structure-function relationships of membrane proteins and protein complexes involved in various aspects of cellular signalling. Among other topics, we are particularly interested in membrane protein complexes in two areas of cellular signalling: (i) the cyclic adenosine monophosphate (cAMP) pathway, (ii) gap junction intercellular communication.
 

1. Structure and function of adenylyl cyclases: central enzymes in cAMP signaling

Membrane adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. As the major effector proteins of G protein-coupled receptors (GPCRs), ACs amplify diverse signals from outside of the cell and translate them into biochemical response inside the cell. Moreover, ACs are capable of integrating different signaling pathways, such as cAMP signaling and calcium signaling pathway. Our research has focused on detailed biochemical and structural studies of various membrane ACs, providing critical insights into their function. These include: (i) AC9 in its autoinhibited state bound to the stimulatory Gαs protein subunit (Qi et al., 2019), (ii) the mycobacterial membrane AC homologue Rv1625c/Cya (Mehta, Khanppnavar et al., 2022), and (iii) calcium/calmodulin-sensitive AC8 in complex with Gαs and calmodulin (Khanppnavar, Schuster et al., 2023). These studies establish a structural framework for understanding how membrane ACs and their macromolecular complexes with various partners initiate and regulate cAMP signaling.

Qi et al., Science, 2019: https://science.sciencemag.org/content/364/6438/389

Mehta, Khappnavar et al., eLife, 2022: https://elifesciences.org/articles/77032

Khanppnavar, Schuster et al., EMBO Reports, 2023: https://www.embopress.org/doi/full/10.1038/s44319-024-00076-y

2. Structural studies of connexin gap junction channels and hemichannels

Gap junction channels (GJCs), formed by connexins, facilitate intercellular communication by linking connexin hemichannels (HCs) on adjacent cells. These channels enable direct metabolic and electrical coupling between cells across various tissues, playing essential roles in numerous physiological and pathological processes. Using cryo-EM analysis combined with biochemistry, cell biology, and electrophysiology approaches, we investigate the molecular mechanisms underlying connexin channel function. Key findings include: (i) the structure of Cx43 in a closed state (Qi, Acosta Gutierrez et al., 2023), (ii) structural characterization of wild-type and Charcot-Marie-Tooth disease-linked mutants of Cx32 GJCs and HCs (Qi, Lavriha, Bayraktar et al., 2023), and (iii) identification of a novel mode of small molecule-mediated inhibition of Cx36 GJCs (Ding, Aureli et al., 2024). These studies provide valuable insights into connexin channel regulation and their roles in health and disease.

Qi, Acosta Gutierrez et al., eLife, 2023: https://elifesciences.org/articles/87616

Qi, Lavriha, Bayraktar et al., Sci Adv, 2023: https://www.science.org/doi/10.1126/sciadv.adh4890

Ding, Aureli et al., Cell Discov, 2024: https://www.nature.com/articles/s41421-024-00691-y

1. Ding X, Aureli S, Vaithia A, Lavriha P, Schuster D, Khanppnavar B, Li X, Blum TB, Picotti P, Gervasio FL, Korkhov VM. Structural basis of connexin-36 gap junction channel inhibition. Cell Discov. 2024 Jun 18;10(1):68. doi: 10.1038/s41421-024-00691-y.

2. Khanppnavar B, Schuster D, Lavriha P, Uliana F, Özel M, Mehta V, Leitner A, Picotti P, Korkhov VM. Regulatory sites of CaM-sensitive adenylyl cyclase AC8 revealed by cryo-EM and structural proteomics. EMBO Rep. 2024 Mar;25(3):1513-1540. doi: 10.1038/s44319-024-00076-y.

3. Qi C, Lavriha P, Bayraktar E, Vaithia A, Schuster D, Pannella M, Sala V, Picotti P, Bortolozzi M, Korkhov VM. Structures of wild-type and selected CMT1X mutant connexin 32 gap junction channels and hemichannels. Sci Adv. 2023 Sep;9(35):eadh4890. doi: 10.1126/sciadv.adh4890.

4. Qi C, Lavriha P, Mehta V, Khanppnavar B, Mohammed I, Li Y, Lazaratos M, Schaefer JV, Dreier B, Plückthun A, Bondar AN, Dessauer CW, Korkhov VM. Structural basis of adenylyl cyclase 9 activation. Nat Commun. 2022 Feb 24;13(1):1045. doi: 10.1038/s41467-022-28685-y.

5. Cannac F, Qi C, Falschlunger J, Hausmann G, Basler K, Korkhov VM. Cryo-EM structure of the Hedgehog release protein Dispatched. Sci Adv. 2020 Apr 15;6(16):eaay7928. doi: 10.1126/sciadv.aay7928.

6. Qi C, Di Minin G, Vercellino I, Wutz A, Korkhov VM. Structural basis of sterol recognition by human hedgehog receptor PTCH1. Sci Adv. 2019 Sep 18;5(9):eaaw6490. doi: 10.1126/sciadv.aaw6490.

7. Qi C, Sorrentino S, Medalia O, Korkhov VM. The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein. Science. 2019 Apr 26;364(6438):389-394. doi: 10.1126/science.aav0778.

Weinert, Adriana (Postdoc)

Vercellino, Irene (Ph.D. Student)

Graeber, Elisabeth (Ph.D. Student)

Cannac, Fabien (Ph.D Student)

Oezel, Merve (Master/Ph.D Student)

Mehta, Ved (Ph.D Student)

Lavriha, Pia (Ph.D Student)

Schuster, Dina (Ph.D Student)