MS – University of Connecticut, Storrs, CT
PhD – Yale University, New Haven, CT
The Kriwacki laboratory seeks to understand the molecular basis of regulation of cell division, apoptosis, and ribosome biogenesis, with special emphasis on the role of intrinsically disordered proteins (IDPs) in these vital biological processes. We apply structural biology and biophysical techniques (NMR spectroscopy, x-ray crystallography, calorimetry, AUC, SAXS/SANS, single-molecule fluorescence, etc.), as well as biochemical and cell biological methods, to study the details of biomolecular mechanisms from the test tube to cells.
We have a long-standing interest in understanding disorder-function relationships for two prototypical disordered proteins, p21 and p27, that are key regulators of the cyclin-dependent kinases (Cdks) that control cell division. We also use p27 as a model system for studies of small molecule/disordered protein interactions. Given the prevalence of disordered proteins in humans, and their frequent association with human diseases, the development of rational approaches to therapeutically modulate IDP function in cells could have a remarkable impact in improving human health.
Another area of interest is to understand the molecular mechanisms through which cytosolic p53 regulates the intrinsic mitochondrial pathway of apoptosis. In a series of studies, we discovered: 1) the molecular mechanisms through which Bcl-xL inhibits cytosolic p53; 2) how this inhibition is relieved by the pro-apoptotic BH3-only protein, PUMA; 3) how p53 directly activates the pro-apoptotic effector protein, BAX; and 4) how a disordered loop within Bcl-xL integrates post-translational modification signals to lower the threshold for BH3-only protein- and p53-dependent apoptosis.
The lab’s current research addresses the role of phase separation in nucleolar structure, dynamics, and function, and its links with neurodegenerative diseases. Three questions are being addressed: 1) how does phase separation within the nucleolus mediate vectorial assembly of ribosomal proteins and RNAs into ribosomal subunits; 2) how are p53-dependent cellular stress responses orchestrated in the liquid-phase setting of the nucleolus; and 3) how is nucleolar structure and function altered by ALS-associated dipeptide repeat polypeptides and how are these alterations associated with ALS pathogenesis?
Forman-Kay JD, Kriwacki RW, Seydoux G. Phase Separation in Biology and Disease. J Mol Biol Sep 10;S0022-2836(18)31054-4, 2018. doi: 10.1016/j.jmb.2018.09.006. [Epub ahead of print] PubMed PMID: 30213727.
Mitrea DM, Chandra B, Ferrolino MC, Gibbs EB, Tolbert M, White MR, Kriwacki RW. Methods for Physical Characterization of Phase-Separated Bodies and Membrane-less Organelles. J Mol Biol Jul 24;S0022-2836(18)30756-3, 2018. doi: 10.1016/j.jmb.2018.07.006. [Epub ahead of print] Review. PubMed PMID: 30017918.
Chen J, Kriwacki RW. Intrinsically Disordered Proteins: Structure, Function and Therapeutics. J Mol Biol Aug 3;430(16):2275-2277, 2018. doi: 10.1016/j.jmb.2018.06.012. Epub 2018 Jun 12. PubMed PMID: 29906412.
Mitrea DM, Kriwacki RW. On the relationship status for Arf and NPM1 - it's complicated. FEBS J Mar;285(5):828-831, 2018. doi: 10.1111/febs.14407. PubMed PMID: 29527821; PubMed Central PMCID: PMC5965676.
Follis AV, Llambi F, Kalkavan H, Yao Y, Phillips AH, Park C-G, Marassi FM, Green DR, Kriwacki RW. Regulation of apoptosis by an intrinsically disordered region of Bcl-xL. Nat Chem Biol Mar 5, 2018. doi: 10.1038/s41589-018-0011-x. [Epub ahead of print] PubMed PMID: 29507390.
Phillips AH, Li O, Gay A, Besson A, Kriwacki RW. Mapping Interactions between p27 and RhoA that Stimulate Cell Migration. J Mol Biol Mar 16;430(6):751-758, 2018. doi: 10.1016/j.jmb.2018.01.017. Epub 2018 Feb 1. PubMed PMID: 29410088.
Mitrea DM, Cika, JA, Stanley, CB, Nourse A, Onucik, PL, Banerjee PR, Phillips, AH, Park, C-G, Deniz AA, Kriwacki RW. Self-interaction of NPM1 Modulates Multiple Mechanism of Liquid-liquid Phase Separation. Nat Commun Feb 26;9(1):842, 2018. doi: 10.1038/s41467-018-03255-3. PubMed PMID: 29483575; PubMed Central PMCID: PMC5827731.
Gibbs EB, Kriwacki RW. Direct Detection of Carbon and Nitrogen Nuclei for High-Resolution Analysis of Intrinsically Disordered Proteins using NMR Spectroscopy. Methods Jan 13;S1046-2023(17)30460-7, 2018. doi: 10.1016/j.ymeth.2018.01.004. [Epub ahead of print] PubMed PMID: 29341926.
Last update: September 2018