Alexei V. Korennykh
James A. Elkins, Jr. '41 Preceptor
Faculty AssistantKaren Plantarich
- Ph.D., University of Chicago
- B.S., Chemistry, Moscow State University, Russia
Research AreaBiochemistry, Biophysics & Structural Biology
Research FocusStructural biology and mechanisms of signal transduction in stress and immune responses
Structural biology and mechanisms of signal transduction in stress and immune responses
Our goal is to understand mechanisms of RNA-dependent signal transduction in immune and endoplasmic reticulum (ER) stress responses. We use X-ray crystallography, biochemistry, biophysics and chemical biology to answer the following key questions: What are the structures of key regulatory proteins, signaling RNA and their complexes? What protein/protein and protein/RNA interactions are important and what roles do they play in signaling? Can we develop synthetic small molecules that modulate these interactions in vitro and in vivo? Can we use such small molecules as tools to understand and dissect the signaling mechanisms and pathways? Can we apply this knowledge to treat tumors and neurodegenerative disorders associated with these responses?
Unfolded protein response
Unfolded protein response (UPR) is a broad signaling network activated when cells cannot keep up with the demand for new protein production. The UPR is activated under diverse circumstances associated with stress and homeostatic imbalance. It is essential for embryo development, B-cell differentiation into antibody-producing plasma cells and uncontrolled proliferation of cancers, with a particularly strong causal connection in multiple myeloma. The entire UPR program involves 7-8% of all eukaryotic genes and is controlled by receptors that sense misfolded proteins.
The most universally conserved receptor of the UPR is a transmembrane protein Ire1. Ire1 has two enzymatic domains, a CDK2 kinase-like protein kinase domain and a regulated ribonuclease (RNase) domain that serves as the main signaling moiety. The RNase carries out a site-specific non-conventional splicing of a transcription factor-encoding mRNA to produce translationally active mRNA. This non-conventional mRNA splicing event is the key signaling point of the UPR and is completely independent of the spliceosome. We aim to understand the mechanisms of regulation and RNA recognition by Ire1.
RNA-dependent pathways in the innate immune system
Our immune system provides two layers of defense: innate immunity and adaptive immunity. The adaptive system can recognize pathogens with exquisite specificity via antibodies, but it responds relatively slowly due to the inherent lag of its feedback and amplification loops. The innate system mounts a less specific, but more rapid response to pathogens by directly recognizing their common attributes (pathogen patterns), such as RNA of viruses. RNA is the target of several receptors in the innate immune system, including protein kinase PKR and Toll-like receptors, which directly sense pathogen's RNA.
We are interested in understanding signal transduction by RNA and regulatory proteins that process or recognize RNA in innate immune response. We aim to gain detailed knowledge of important and presently poorly understood mechanisms, and have a far-reaching goal of being able to control them in disorders associated with aberrant immune signaling. Of particular interest are certain tumors, autoimmune and atopic diseases, including lupus erythematosus and asthma, as well as neurodegenerative diseases, such as multiple sclerosis.
The human microbiome encodes resistance to the antidiabetic drug acarbose. Nature. 2021 ;600(7887):110-115. .
Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L. Proc Natl Acad Sci U S A. 2021 ;118(46). .
Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response. Mol Cell. 2019 ;75(6):1218-1228.e6. .
The metabolites NADP and NADPH are the targets of the circadian protein Nocturnin (Curled). Nat Commun. 2019 ;10(1):2367. .
Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L. Proc Natl Acad Sci U S A. 2019 ;116(6):2103-2111. .
Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3. Proc Natl Acad Sci U S A. 2015 ;112(13):3949-54. .
Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response. Science. 2014 ;343(6176):1244-8. .
Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1. Proc Natl Acad Sci U S A. 2013 ;110(5):1652-7. .
Innate immune messenger 2-5A tethers human RNase L into active high-order complexes. Cell Rep. 2012 ;2(4):902-13. .
Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol. 2012 ;28:251-77. .
Dr. Alexei Korennykh is an Associate Professor of Molecular Biology at Princeton University. He is interested in structural and cell biology of pathways mediated by dsRNA and by RNA-processing receptors that mediate innate immunity to viruses and bacteria, cell proliferation, tumor progression, obesity and response to stress caused by imbalance of protein folding. Dr. Korennykh received his BS degree in Chemistry at Moscow State University (Russia). During his PhD work with Joe Piccirilli at the University of Chicago (1999-2005), he focused on recognition of RNA and eukaryotic ribosomes by enzymes that stop translation via structure-specific modification of large ribosomal RNA. For his postdoctoral work (2006-2011), he joined the laboratory of Peter Walter at University of California, San Francisco (UCSF). At UCSF he worked on a signaling mechanism by which cells deal with protein misfolding. This mechanism is called Unfolded Protein Response and involves upregulation of hundreds of protein folding genes. In some eukaryotic cells, such as yeasts, the entire UPR program is controlled by a single receptor kinase/ribonuclease Ire1 in the membrane of endoplasmic reticulum (ER). Dr. Korennykh found that Ire1 is activated by assembling into a high-order complex, co-developed synthetic small molecule modulators of Ire1, and determined the crystal structure of this high-order complex with a synthetic small molecule modulator bound. This work received UCSF Dean's 2010 Postdoctoral Prize and served as the basis for two international patent applications. His PhD and postdoctoral work was supported by the Burroughs Wellcome Fund and by The Jane Coffin Childs Memorial Fund for Medical Research. Dr. Korennykh's current work focuses on structural biology of the OAS/RNase L axis of the innate immune system and is supported by NIH (R01), Princeton University Office of Technology Management, Sydney Kimmel Foundation, and Burroughs Wellcome Fund.
- Innovation Award, Department of Molecular Biology, Princeton University
- James A. Elkins, Jr. '41 Preceptorship , The Elkins Foundation
- General Biology Award , Biomed Central