We are an interdisciplinary Research Laboratory based in the Ben Gurion University of the Negev, Beer-Sheva, Israel. In collaboration with other laboratories at the BGU and from outside, we investigate novel concepts that underlie the complexities of neurodegenerative diseases.
Our Current Focus
Aerobic metabolism as driving force of CNS evolution and its susceptibility to neurodegenerative diseases
Despite different phenotypic manifestations, there are similarities in the molecular basis of major neurodegenerative diseases (NDs). CNS has evolved to be robust against the hazard of reactive oxygen species (ROS), a common perturbation aerobic organisms are confronted with. The trade-off of robustness is system’s fragility against rare and unexpected perturbations. Identifying the points of CNS fragility is key for understanding etiology of NDs. We postulated that the 'primate differential redoxome' (PDR), an assembly of proteins that contain cysteine residues (redox switches) present only in the primate orthologues of mammals, is likely to associate with an added level of regulatory functionalities, which enhanced CNS robustness against ROS and facilitated evolution. The PDR contains multiple deterministic and susceptibility factors of major NDs, which cluster to form coordinated redox networks regulating various cellular processes.
We employ a variety of experimental approaches, including cysteine redox proteomics and bioinformatics tools to corroborate the involvement of the PDR in the pathogenesis of major ND, such as Alzheimer’s, Parkinson’s and Huntington's diseases The goal is to identify the major points of CNS fragility, which is key for the development of mechanism-based therapeutics.
Targeting the pathogenic epitope of misfolded SOD1 to treat/prevent ALS
Amyotrophic lateral sclerosis (ALS) – is a neurodegenerative disease characterized by a gradual degeneration and death of motor neurons (MNs). A prominent ALS pathogenic protein is a ubiquitous enzyme superoxide dismutase 1 (SOD1), which is responsible for a significant fraction of familial and probably some sporadic cases. In ALS, SOD1 undergoes a noxious structural transformation, so-called misfolding, as a result of mutation or environmental stress, such as oxidative stress, rendering SOD1 neurotoxic. We have identified a pathogenic epitope exposed in misfolded SOD1, which appears to contribute to SOD1 neurotoxicity in ALS. Our strategy is to target this pathogenic SOD1 epitope, using a wide variety of pharmacological tools, in order to develop novel mechanism-based therapeutics to treat/prevent ALS.
Research Opportunities at Engel's lab
As a growing Research Laboratory, we are currently looking to expand our team. Below is a list of open positions. Please get in touch with any questions about the application process.
Research opportunities at Engel's lab
We welcome motivated students for research projects, M.Sc. and Ph.D studies.
We also welcome outstanding international students (including refugees) with an M.Sc. in Life Sciences or similar disciplines to join the lab as Ph.D. students at the BGU. The Ph.D. program lasts four years, during which the students receive full fellowships.
We also offer Postdoc positions at the lab.
To apply, please send a letter describing your research experience and interests, and a CV (including transcripts) to Prof. Stanislav (Stas) Engel (firstname.lastname@example.org).
1. M. Meltzer, T. Zvagelsky, U. Hadad, N. Papo, S. Engel. Yeast-based directed-evolution for high-throughput structural stabilization of G protein-coupled receptors (GPCRs). Sci Rep 12, 8657 (2022).
2. S. Bakavayev, S. Argueti, N. Venkatachalam, G. Yehezkel, A. Stavsky, Z. Barak, A. Israelson, S. Engel. The exposure of β6/β7-loop in Zn/Cu-superoxide dismutase (SOD1) is coupled to metal loss and is transiently reversible during misfolding. ACS Chemical Neuroscience, 12(1):49-62 (2021)
3. N. Venkatachalam, S. Bakavayev, D. Engel, Z. Barak, S. Engel, Primate Differential Redoxome (PDR) – a paradigm for understanding neurodegenerative diseases, Redox Biology, 36:101683 (2020)
4. Bakavayev S, Chetrit N, Zvagelsky T, Mansour R, Vyazmensky M, Barak Z, Israelson A, Engel S. Cu/Zn-superoxide dismutase and wild-type like fALS SOD1 mutants produce cytotoxic quantities of H2O2 via cysteine-dependent redox short-circuit. Sci Rep. 2019 Jul 25;9(1):10826. doi: 10.1038/s41598-019-47326-x.
5. Banerjee V, Oren O, Dagan B, Taube R, Engel S, Papo N. An Engineered Variant of the B1 Domain of Protein G Suppresses the Aggregation and Toxicity of Intra- and Extracellular Aβ42. ACS Chem Neurosci. 2019 Mar 20;10(3):1488-1496. doi: 10.1021/acschemneuro.8b00491.
6. Kuttner YY, Engel S. Complementarity of stability patches at the interfaces of protein complexes: Implication for the structural organization of energetic hot spots. Proteins. 2018 Feb;86(2):229-236. doi: 10.1002/prot.25430.
7. Shvil N, Banerjee V, Zoltsman G, Shani T, Kahn J, Abu-Hamad S, Papo N, Engel S, Bernhagen J, Israelson A. MIF inhibits the formation and toxicity of misfolded SOD1 amyloid aggregates: implications for familial ALS. Cell Death Dis. 2018 Jan 25;9(2):107. doi: 10.1038/s41419-017-0130-4.
8. Banerjee V, Oren O, Ben-Zeev E, Taube R, Engel S, Papo N. A computational combinatorial approach identifies a protein inhibitor of superoxide dismutase 1 misfolding, aggregation, and cytotoxicity. J Biol Chem. 2017 Sep 22;292(38):15777-15788. doi: 10.1074/jbc.M117.789610.
9. Press O, Zvagelsky T, Vyazmensky M, Kleinau G, Engel S. Construction of Structural Mimetics of the Thyrotropin Receptor Intracellular Domain. Biophys J. 2016 Dec 20;111(12):2620-2628. doi: 10.1016/j.bpj.2016.11.002.
10. Banerjee V, Shani T, Katzman B, Vyazmensky M, Papo N, Israelson A, Engel S. Superoxide Dismutase 1 (SOD1)-Derived Peptide Inhibits Amyloid Aggregation of Familial Amyotrophic Lateral Sclerosis SOD1 Mutants. ACS Chem Neurosci. 2016 Nov 16;7(11):1595-1606. doi: 10.1021/acschemneuro.6b00227.
11. Osman R, Mezei M, Engel S. The role of protein "Stability patches" in molecular recognition: A case study of the human growth hormone-receptor complex. J Comput Chem. 2016 Apr 15;37(10):913-9. doi: 10.1002/jcc.24276.
12. Kuzmina A, Vaknin K, Gdalevsky G, Vyazmensky M, Marks RS, Taube R, Engel S. Functional Mimetics of the HIV-1 CCR5 Co-Receptor Displayed on the Surface of Magnetic Liposomes. PLoS One. 2015;10(12):e0144043. doi: 10.1371/journal.pone.0144043. eCollection 2015.
13. Katzman B, Vyazmensky M, Press O, Volokita M, Engel S. Tethered ribozyme ligation enables detection of molecular proximity in homogeneous solutions. Biotechnol J. 2015 Mar;10(3):379-85. doi: 10.1002/biot.201400551.
14. Kuttner YY, Nagar T, Engel S. Surface dynamics in allosteric regulation of protein-protein interactions: modulation of calmodulin functions by Ca2+. PLoS Comput Biol. 2013 Apr;9(4):e1003028. doi: 10.1371/journal.pcbi.1003028.
15. Kuttner YY, Engel S. Protein hot spots: the islands of stability. J Mol Biol. 2012 Jan 13;415(2):419-28. doi: 10.1016/j.jmb.2011.11.009.
Thank you for your interest in our research. Get in touch with us for any questions or comments regarding our work and publications.
Engel's Lab, Dept. of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel