Molecular Biology Faculty
|Korennykh Research Lab|
Schultz Lab, 216
Lab (609) 258-6071
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.
General Biology Award from BioMed Central, 2011
Donovan J, Whitney G, Rath S, Korennykh A. (2015) Structural mechanism of sensing long dsRNA via a noncatalytic domain in human oligoadenylate synthetase 3. Proc Natl Acad Sci. 112:3949-54. Pubmed
Han Y, Donovan J, Rath S, Whitney G, Chitrakar A, Korennykh A. (2014) Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response. Science. 343:1244-8. Pubmed
Donovan J, Dufner M, Korennykh A. (2013) Structural basis for cytosolic double-stranded RNA surveillance by human OAS1. Proc Natl Acad Sci. 110: 1652-57. PubMed
Han Y, Whitney G, Donovan J, Korennykh A. (2012) Innate immune messenger 2-5A tethers human RNase L into active high-order complexes. Cell Rep. 2: 902-13. Pubmed
Korennykh A1, Walter P. (2012) Structural basis of the unfolded protein response. Annu Rev Cell Dev Biol. 28: 251-77. Pubmed
Korennykh AV, Korostelev AA, Egea PF,...Walter P. (2011) Structural and functional basis for RNA cleavage by Ire1. BMC Biol. 9: 47. PubMed
Korennykh AV, Egea PF, Korostelev AA,...Walter P. (2011) Cofactor-mediated conformational control in the bifunctional kinase/RNase Ire1. BMC Biol. 9: 48. PubMed
Rubio C, Pincus D, Korennykh A, Schuck S, El-Samad H, Walter P. (2011) Homeostatic adaptation to endoplasmic reticulum stress depends on Ire1 kinase activity. J Cell Biol. 193: 171-84. PubMed
Plantinga MJ, Korennykh AV, Piccirilli JA, Correll CC. (2011) The ribotoxin restrictocin recognizes its RNA substrate by selective engagement of active site residues. Biochemistry. 50: 3004-13. PubMed
Li H1, Korennykh AV, Behrman SL, Walter P. (2010) Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci. 107: 16113-18. Pubmed
Li H, Korennykh AV, Behrman SL, Walter P. (2010) Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci. 107: 16113-18. PubMed
Korennykh AV, Egea PF, Korostelev AA,...Walter P. (2009) The unfolded protein response signals through high-order assembly of Ire1. Nature. 457: 687-93. PubMed
Aragón T, van Anken E, Pincus D,...Korennykh AV,...Walter P. (2009) Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature. 457: 736-40. PubMed
Plantinga MJ, Korennykh AV, Piccirilli JA, Correll CC. (2008) Electrostatic interactions guide the active site face of a structure-specific ribonuclease to its RNA substrate. Biochemistry. 47: 8912-18. PubMed
Korennykh AV, Plantinga MJ, Correll CC, Piccirilli JA. (2007) Linkage between substrate recognition and catalysis during cleavage of sarcin/ricin loop RNA by restrictocin. Biochemistry. 46: 12744-56. PubMed
Korennykh AV, Correll CC, Piccirilli JA. (2006) Evidence for the importance of electrostatics in the function of two distinct families of ribosome inactivating toxins. RNA. 13: 1391-96. PubMed
Korennykh AV, Piccirilli JA, Correll CC. (2006) The electrostatic character of the ribosomal surface enables extraordinarily rapid target location by ribotoxins. Nat Struct Mol Biol. 13: 436-43. PubMed
Shcherbakova T, Korennykh, A, Van Langen L, Sheldon R, Švedas V. (2004) Use of high acyl donor concentrations leads to penicillin acylase inactivation in the course of peptide synthesis. J Molec Catalysis B: Enzymatic. 31: 63-65. Science Direct
Khimiuk A, Korennykh A, Van Langen L, Van Rantwijk F, Sheldon R, Švedas V. (2003) Penicillin acylase-catalyzed peptide synthesis in aqueous medium: a chemo-enzymatic route to stereoisomerically pure diketopiperazines. Tetrahedron: Asymmetry. 14: 3123-28.