Dr. Krulwich is the Sharon & Frederick A. Klingenstein-Nathan G. Kase, MD Professor, Program Director of the Mount Sinai Post-Baccalaureate Research Education Program and of the pre-doctoral Integrated Pharmacological Sciences Training Program. She is also Education and Outreach Core Director for the Systems Biology Center New York. Dr. Krulwich's research programs are described under the Krulwich Laboratory.
Alkaliphilic Bacillus, Membrane Proteins/Channels, Oxidative Phosphorylation, Staphylococcus Aureus, Transporters
Multi-Disciplinary Training Area
Biophysics and Systems Pharmacology [BSP]
BA, Goucher College
MS, PhD, NSF Predoctoral Fellowship, University of Wisconsin
NSF Postdoctoral Fellowship, Albert Einstein College of Medicine
Summary of Research Interests
The Krulwich Laboratory studies ion-translocating membrane transporters in bacterial cells are critical participants in the physiology of both pathogens and non-pathogenic bacteria of ecological interest.
Oxidative phosphorylation at high pH: a model system for probing the proton path during energization of ATP synthesis by the respiratory chain. Biochemical, molecular and biophysical studies of OXPHOS in mutant and wild-type cells, membranes and purified systems test the hypothesis of sequestered proton transfer during OXPHOS that depend upon special adaptations of the ATP synthase and respiratory chain complexes and may also depend upon specific membrane phospholipid content. In collaboration with Thomas Meier’s research group (Max Planck Biophysics Institute, Frankfurt, Germany), structural studies of the ATP synthase rotor are unraveling properties that relate to specific adaptations of the alkaliphile synthase as well as properties that are likely to be found more broadly among bacterial ATP synthases.
Mrp-type monovalent cation/proton antiporter systems: basis and roles for the unusual complexity of this major bacterial antiporter system. In collaboration with Masahiro Ito's lab (Toyo University, Japan), we study the catalytic properties, physiological roles and structural features of Mrp systems from bacteria such as pathogenic Staphylococcus aureus and non-pathogenic Bacillus species. We are testing the hypothesis that Mrp proteins form a complex that is a "consortium" of transporters that includes monovalent cation/proton antiporters and which function synergistically. We are also investigating a systems response by bacterial cells in which stresses that lead to an acute increase in Mrp function, thereby acutely reducing the membrane potential that energizes antiport, sets in motion a series of events that leads to a membrane potential that is even higher than in the absence of the original stress(es).
Structure-function studies of the tetracycline efflux protein, TetL, that supports tetracycline-resistance in Gram-positive bacteria is being investigated with the goal of achieving information that will further define the catalytic capacities of the transporter and will inform design of inhibitors of the antibiotic-resistance protein. This work is part of a collaboration with Da-Neng Wang’s laboratory (Skirball Institute, NYU).
Preiss L, Langer JD, Hicks DB, Liu J, Yildiz O, Krulwich TA, Meier T. The c-ring ion binding site of the ATP synthase from Bacillus pseudofirmus OF4 is adapted to alkaliphilic lifestyle. Molecular Microbiology 2014 Jun; 92(5): 973-984.
Liu J, Ryabichko S, Bogdanov M, Fackelmayer OJ, Dowhan W, Krulwich TA. Cardiolipin is dispensable for oxidative phosphorylation and non-fermentative growth of alkaliphilic Bacillus pseudofirmus OF4. Journal of Biological Chemistry 2014 Jan; 289(5): 2960-2971.
Morino M, Suzuki T, Ito M, Krulwich TA. Purification and functional reconstitution of a seven-subunit mrp-type na+/h+ antiporter. Journal of Bacteriology 2014 Jan; 196(1): 28-35.
Krulwich TA, Ito M. Prokaryotic alkaliphiles. The Prokaryotes, Rosenberg, E., DeLong, E.F., Lory, S., Stackebrandt, E., Thompson, F. (Eds.) Springer New York 2013; 1(4).
Price-Whelan A, Poon CK, Benson MA, Eidem TT, Roux CM, Boyd JM, Dunman PM, Torres VJ, Krulwich TA. Transcriptional profiling of Staphylococcus aureus during growth in 2 M NaCl leads to clarification of physiological roles for Kdp and Ktr K+ uptake systems. mBio 2013; 4(4): e00407-13.
Preiss L, Klyszejko AL, Hicks DB, Liu J, Fackelmayer OJ, Yildiz Ö, Krulwich TA, Meier T. The c-ring stoichiometry of ATP synthase is adapted to cell physiological requirements of alkaliphilic Bacillus pseudofirmus OF4. Proc Natl Acad Sci U S A 2013 May; 110(19): 7874-7879.
Liu J, Hicks DB, Krulwich TA. Roles of AtpI and two YidC-type proteins from alkaliphilic Bacillus pseudofirmus OF4 in ATP synthase assembly and nonfermentative growth. Journal of Bacteriology 2013 Jan; 195(2): 220-230.
Janto B, Ahmed A, Ito M, Liu J, Hicks DB, Pagni S, Fackelmayer OJ, Smith TA, Earl J, Elbourne LD, Hassan K, Paulsen IT, Kolstø AB, Tourasse NJ, Ehrlich GD, Boissy R, Ivey DM, Li G, Xue Y, Ma Y, Hu FZ, Krulwich TA. Genome of alkaliphilic Bacillus pseudofirmus OF4 reveals adaptations that support the ability to grow in an external pH range from 7.5 to 11.4. Environmental Microbiology 2011 Dec; 13(12): 3289-3309.
Liu J, Fackelmayer OJ, Hicks DB, Preiss L, Meier T, Sobie EA, Krulwich TA. Mutations in a helix-1 motif of the ATP synthase c-subunit of Bacillus pseudofirmus OF4 cause functional deficits and changes in the c-ring stability and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biochemistry 2011 Jun; 50(24): 5497-5506.
Krulwich TA, Sachs G, Padan E. Molecular aspects of bacterial pH sensing and homeostasis. Nature Reviews Microbiology 2011 May; 9(5): 330-343.
Hoffmann J, Sokolova L, Preiss L, Hicks DB, Krulwich TA, Morgner N, Wittig I, Schägger H, Meier T, Brutschy B. ATP synthases: cellular nanomotors characterized by LILBID mass spectrometry. Physical Chemistry Chemical Physics 2010 Nov; 12(41): 13375-13382.
Fujisawa M, Fackelmayer OJ, Liu J, Krulwich TA, Hicks DB. The ATP synthase a-subunit of extreme alkaliphiles is a distinct variant: mutations in the critical alkaliphile-specific residue Lys-180 and other residues that support alkaliphile oxidative phosphorylation. Journal of Biological Chemistry 2010 Oct; 285(42): 32105-32115.
Preiss L, Yildiz O, Hicks DB, Krulwich TA, Meier T. A new type of proton coordination in an F(1)F(o)-ATP synthase rotor ring. PLoS Biology 2010; 8(8): e1000443.
Morino M, Natsui S, Ono T, Swartz TH, Krulwich TA, Ito M. Single site mutations in the hetero-oligomeric Mrp antiporter from alkaliphilic Bacillus pseudofirmus OF4 that affect Na+/H+ antiport activity, sodium exclusion, individual Mrp protein levels, or Mrp complex formation. Journal of Biological Chemistry 2010 Oct; 285(40): 30942-30950.
Hicks DB, Liu J, Fujisawa M, Krulwich TA. F1F0-ATP synthases of alkaliphilic bacteria: lessons from their adaptations. Biochimica et Biophysica Acta 2010 Aug; 1797(8): 1362-1377.
Krulwich TA, Hicks DB, Ito M. Cation/proton antiporter complements of bacteria: why so large and diverse?. Molecular Microbiology 2009 Oct; 74(2): 257-260.
Liu J, Fujisawa M, Hicks DB, Krulwich TA. Characterization of the Functionally Critical AXAXAXA and PXXEXXP Motifs of the ATP Synthase c-Subunit from an Alkaliphilic Bacillus. Journal of Biological Chemistry 2009 Mar; 284(13): 8714-8725.
Terahara N, Krulwich TA, Ito M. Mutations alter the sodium versus proton use of a Bacillus clausii flagellar motor and confer dual ion use on Bacillus subtilis motors. Proc Natl Acad Sci U S A 2008 Sep; 105(38): 14359-14364.
Morino M, Natsui S, Swartz TH, Krulwich TA, Ito M. Single gene deletions of mrpA to mrpG and mrpE point mutations affect activity of the Mrp Na+/H+ antiporter of alkaliphilic Bacillus and formation of hetero-oligomeric Mrp complexes. Journal of Bacteriology 2008 Jun; 190(12): 4162-4172.
Liu J, Krulwich TA, Hicks DB. Purification of two putative type II NADH dehydrogenases with different substrate specificities from alkaliphilic Bacillus pseudofirmus OF4. Biochimica et Biophysica Acta 2008 May; 1777(5): 4162-4172.
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