Richard Kriwacki, PhD
Richard W. Kriwacki, PhD

Richard W. Kriwacki, PhD

Member, St. Jude Faculty

  • Co-Leader, Cancer Biology Program
  • Adjunct Associate Professor, Department of Molecular Sciences, UT Health Science Center, Memphis

Departments

Education

MS – University of Connecticut, Storrs, CT
PhD – Yale University, New Haven, CT

Research Interests

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?

Kriwacki Research Lab

Contact Information

Richard W. Kriwacki, PhD Structural Biology MS 311, Room M7434 St. Jude Children's Research Hospital 262 Danny Thomas Place Memphis, TN 38105-3678

St. Jude Faculty List

Related Topics

News Releases

Selected Publications

Dar F, Cohen SR, Mitrea DM, Phillips AH, Nagy G, Leite WC, Stanley CB, Choi JM*, Kriwacki RW*, Pappu RV*. Biomolecular condensates form spatially inhomogeneous network fluids. Nat Commun. 2024 Apr 22;15(1):3413.  doi: 10.1038/s41467-024-47602-z. (*co-corresponding authors)     

Lemke EA*, Babu MM*, Kriwacki RW*, Mittag T*, Pappu RV*, Wright PE*, Forman-Kay JD*. Intrinsic disorder: A term to define the specific physicochemical characteristic of protein conformational heterogeneity. Mol Cell. 2024 Apr 4;84(7):1188-1190. doi: 10.1016/j.molcel.2024.02.024.  (*co-corresponding authors)

Shirnekhi HK, Chandra B, Kriwacki RW. Dissolving Fusion Oncoprotein Condensates to Reverse Aberrant Gene Expression. Cancer Res Oct 13;83(20):3324-3326, 2023. doi: 10.1158/0008-5472.CAN-23-2769. PMID: 37828859

Tripathi S, Shirnekhi HK, Gorman SD, Chandra B, Baggett DW, Park CG, Somjee R, Lang B, Hosseini SMH, Pioso BJ, Li Y, Iacobucci I, Gao Q, Edmonson MN, Rice SV, Zhou X, Bollinger J, Mitrea DM, White MR, McGrail DJ, Jarosz DF, Yi SS, Babu MM, Mullighan CG, Zhang J, Sahni N, Kriwacki RW. Defining the condensate landscape of fusion oncoproteins. Nat Commun Sep 28;14(1):6008, 2023. doi: 10.1038/s41467-023-41655-2. PMID: 3777042. PMCID: PMC10539325

Riback JA, Eeftens JM, Lee DSW, Quinodoz SA, Donlic A, Orlovsky N, Wiesner L, Beckers L, Becker LA, Strom AR, Rana U, Tolbert M, Purse BW, Kleiner R, Kriwacki R, Brangwynne CP. Viscoelasticity and advective flow of RNA underlies nucleolar form and function. Mol Cell Sep 7;83(17):3095-3107.e9, 2023. doi: 10.1016/j.molcel.2023.08.006. PMID: 37683610

Shirnekhi HK, Chandra B, Kriwacki RW. The Role of Phase-Separated Condensates in Fusion Oncoprotein–Driven Cancers. Ann Rev Cancer Biology 7:73-91, 2023. https://doi.org/10.1146/annurev-cancerbio-061421-122050.

Boeynaems S, Chong S, Gsponer J, Holt L, Milovanovic D, Mitrea DM, Mueller-Cajar O, Portz B, Reilly JF, Reinkemeier CD, Sabari BR, Sanulli S, Shorter J, Sontag E, Strader L, Stachowiak J, Weber SC, White M, Zhang H, Zweckstetter M, Elbaum-Garfinkle S, Kriwacki R. Phase Separation in Biology and Disease; Current Perspectives and Open Questions. J Mol Biol Mar 1;435(5):167971, 2023. doi: 10.1016/j.jmb.2023.167971. PMID: 36690068. PMCID: PMC9970028

Ugolini I, Bilokapic S, Ferrolino M, Teague J, Yan Y, Zhou X, Deshmukh A, White M, Kriwacki RW, Halic M. Chromatin localization of nucleophosmin organizes ribosome biogenesis. Mol Cell Dec 1;82(23):4443-4457.e9, 2022. doi: 10.1016/j.molcel.2022.10.033. PMID: 3642363. PMCID: PMC9949351

Baggett DW, Medyukhina A, Tripathi S, Shirnekhi HK, Wu H, Pounds SB, Khairy K, Kriwacki R. An Image Analysis Pipeline for Quantifying the Features of Fluorescently Labeled Biomolecular Condensates in Cells. Front Bioinform Jun 6;2:897238, 2022. doi: 10.3389/fbinf.2022.897238. PMID: 36304323. PMCID: PMC9580871

Chandra B, Kriwacki R. Charting the human disease condensate dysregulome. Dev Cell Jul 25;57(14):1677-1679, 2022. doi: 10.1016/j.devcel.2022.07.001. PMID: 35901780

Guy C, Mitrea DM, Chou PC, Temirov J, Vignali KM, Liu X, Zhang H, Kriwacki R, Bruchez MP, Watkins SC, Workman CJ, Vignali DAA. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat Immunol May;23(5):757-767, 2022. doi: 10.1038/s41590-022-01176-4. PMID: 35437325. PMCID: PMC9106921 

Chandra B, Michmerhuizen NL, Shirnekhi HK, Tripathi S, Pioso BJ, Baggett DW, Mitrea DM, Iacobucci I, White MR, Chen J, Park CG, Wu H, Pounds S, Medyukhina A, Khairy K, Gao Q, Qu C, Abdelhamed S, Gorman SD, Bawa S, Maslanka C, Kinger S, Dogra P, Ferrolino MC, Di Giacomo D, Mecucci C, Klco JM, Mullighan CG, Kriwacki RW. Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation. Cancer Discov Apr 1;12(4):1152-1169, 2022. doi: 10.1158/2159-8290.CD-21-0674. PMID: 34903620. PMCID: PMC8983581

Pinto EM, Maxwell KN, Halalsheh H, Phillips A, Powers J, MacFarland S, Walsh MF, Breen K, Formiga MN, Kriwacki R, Nichols KE, Mostafavi R, Wang J, Clay MR, Rodriguez-Galindo C, Ribeiro RC, Zambetti GP. Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants. Mol Cancer Res Feb;20(2):207-216, 2022. doi: 10.1158/1541-7786.MCR-21-0583. PMID: 34675114. PMCID: PMC8816887 

Iconaru LI, Das S, Nourse A, Shelat AA, Zuo J, Kriwacki RW. Small Molecule Sequestration of the Intrinsically Disordered Protein, p27Kip1, Within Soluble Oligomers. J Mol Biol Sep 3;433(18):167120, 2021. doi: 10.1016/j.jmb.2021.167120. PMID: 34197833.  PMCID: PMC8658733 

Elbaum-Garfinkle S, Kriwacki RW. Phase Separation in Biology & Disease: The next chapter. J Mol Biol Jun 11;433(12):166990, 2021. doi: 10.1016/j.jmb.2021.166990. PMID: 33857471

Riback JA, Zhu L, Ferrolino MC, Tolbert M, Mitrea DM, Sanders DW, Wei MT, Kriwacki RW*, Brangwynne CP*. Composition-dependent thermodynamics of intracellular phase separation. Nature May;581(7807):209-214, 2020. doi: 10.1038/s41586-020-2256-2. PMID: 32405004. PMCID: PMC7733533 (*co-corresponding author)

Phillips AH, Kriwacki RW. Intrinsic protein disorder and protein modifications in the processing of biological signals. Curr Opin Struct Biol Feb: 60:1-6, 2020. doi: 10.1016/j.sbi.2019.09.003. PMID: 31629249

Gibbs E, Perrone B, Hassan A, Kummerle R, Kriwacki R. NPM1 ehibits structural and dynamic heterogeneity upon phase separation with the p14ARF tumor suppressor. J Magn Reson Jan:310:106646, 2020. doi: 10.1016/j.jmr.2019.106646. PMID: 31751897. PMCID: PMC6934896 

White MR, Mitrea DM, Zhang P, Stanley CB, Cassidy DE, Nourse A, Phillips AH, Tolbert M, Taylor JP, Kriwacki RW. C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function. Mol Cell May 16;74(4):713-728.e6, 2019. doi: 10.1016/j.molcel.2019.03.019. PMID: 30981631. PMCID: PMC6525025 

Tsytlonok M, Sanabria H, Wang Y, Felekyan S, Hemmen K, Phillips AH, Yun MK, Waddell MB, Park CG, Vaithiyalingam S, Iconaru L, White SW, Tompa P, Seidel CAM, Kriwacki R. Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation. Nat Commun Apr 11;10(1):1676, 2019. doi: 10.1038/s41467-019-09446-w. PMID: 30976006. PMCID: PMC6459857 

Beveridge R, Migas LG, Das RK, Pappu RV, Kriwacki RW, Barran PE. Ion Mobility Mass Spectrometry Uncovers the Impact of the Patterning of Oppositely Charged Residues on the Conformational Distributions of Intrinsically Disordered Proteins. J Am Chem Soc Mar 27;141(12):4908-4918, 2019. doi: 10.1021/jacs.8b13483. PMID: 30823702. PMCID: PMC6488185 

Beveridge R, Migas LG, Kriwacki RW, Barran PE. Ion Mobility Mass Spectrometry Measures the Conformational Landscape of p27 and its Domains and how this is Modulated upon Interaction with Cdk2/cyclin A. Angew Chem Int Ed Engl Mar 4;58(10):3114-3118, 2019. doi: 10.1002/anie.201812697. PMID: 30570821. PMCID: PMC7122115 

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: November 2023

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