I graduated from Moscow University with a M.S. degree in bioorganic chemistry and obtained a Ph.D. degree in biophysics from the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow. I received postdoctoral training in biophysics and protein folding with Wayne Bolen at University of Texas Medical Branch and on prions with Nobel laureate Stanley Prusiner at UCSF. In UTMB, I established a pioneering approach for folding natively unfolded proteins. With Dr. Bolen, we described a new thermodynamic force that contributes to protein folding and stability more than 40 years after Kauzmann introduced four basic thermodynamic forces responsible for protein folding. As a postdoctoral fellow with Stanley Prusiner, I laid the ground work on synthetic prions and showed for the very first time that the transmissible prion disease can be induced in animals using amyloid fibrils prepared in vitro.
Image 1: High resolution atomic force microscopy image of prion protein amyloid fibrils
Research in my laboratory focuses on elucidating molecular mechanisms responsible for prion replication and structure of infectious forms of the prion protein.
Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative disorders that can arise spontaneously, be inherited or acquired through transmission. The transmissible agent of prion diseases devoid of nucleic acids, but instead consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism.
Current studies in our laboratory are focused on the following topics: (i) establishing a relationship between prion structure and infectivity; elucidating molecular and structural requirements essential for the prion protein to acquire infectious conformation; (ii) defining molecular features responsible for prion strain diversity; (iii) developing new imaging approaches for probing conformation and composition within individual PrP particles; (iv) developing Protein Misfolding Cyclic Amplification-based approach for ultra-sensitive and robust detection and amplification of prions.
In the past few years, our laboratory introduced several innovative approaches and concepts, including a new approach for assessing conformation within individual amyloid fibrils and a novel concept on conformational switching within individual fibrils. Our most recent studies introduced a new hypothesis that transmissible prion diseases can be triggered by structures substantially different from that of authentic PrPSc. This new concept has important implications for understanding the genesis of infectious prion structures and the etiology of transmissible prion diseases.
Image 2: Prion plaques in a brain of animal infected with synthetic prions produced in vitro
Lab Techniques and Equipment:
Ongoing studies in our laboratory include biochemical, molecular imaging, structural, cellular, pathological and experimental animal approaches to understand the mechanisms by which prions replicate, to define molecular features responsible for prion infectivity and prion strain diversity.
Our laboratory is equipped with Atomic Force Microscope PicoLE combined with the inverted fluorescence microscop, CD spectrophotometer J- 810 (Jacso); FTIR spectrometer Tensor 27 equipped (Bruker); fluorimeter FlouroMax-3 (Jobin Yvon); dynamic light scattering DynaPro-MS/X (Protein Solutions); HPLC system with fluorescence and photodiode detectors (Shimadzu); FPLC system Akta prime (Amersham); fluorescence inverted microscope TE-2000 (Nikon); automated sonicators Misonix S-4000.
We collaborate with leading experts on amyloid structure (Robert Tycko, NIH), prion pathology (Herbert Budka, Austria; Martin Jeffrey, UK) and amyloid imaging (Peter Nilsson, Sweden).
- Natallia Makarava, Research Supervisor
- Elizaveta Katorcha, Postdoctoral Fellow
- Saurabh Srivastava, Postdoctoral Fellow
- Nina Klimova, graduate student
- Regina Savtchenko, Research Assistant
- Daryl Butler, Research Specialist Laboratory Animals
Makarava, N., Kovacs, G.G., Savtchenko, R., Alexeeva , I., Ostapchenko, V., Budka, H., Rohwer , R.G., Baskakov, I.V. 2012 A New Mechanism for Transmissible Prion Diseases, J. Neurosci, 23 May .32(21) p 7345-7355.
Makarava, N., Savtchenko, R., Alexeeva , I., Rohwer , R.G., Baskakov, I.V., 2012 Fast and ultrasensitive method for quantitating prion infectivity titre, Nature Commun. V. 3, p741.
Makarava, N., Kovacs, G.G., Savtchenko, R., Alexeeva , I., Budka, H., Rohwer , R.G., Baskakov, I.V., 2011 Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease, PLoS Pathogen, V. 7, p.31002419.
Lee, Y. J., Savtchenko, R., Ostapchenko, V.G., Makarava, N., Baskakov, I.V. 2011 Molecular structure of amyloid fibrils controls the relationship between size and toxicity. PLoS One, V6(5); e20244
Gonzalez-Montalban, N., Makarava, N., Savtchenko, R., Baskakov, I.V. 2011 Relationship between conformational stability and amplification efficiency of prions. Biochemistry, V50, p7933-7940.
Gonzalez-Montalban, N., Makarava, N., Ostapchenko, V.G., Savtchenko, R., Alexeeva , I., Rohwer , R.G., Baskakov, I.V. 2011 Highly efficient protein misfolding cyclic amplification, PLoS Pathog. V.7(2), e1991277
Tycko R, Savtchenko R, Ostapchenko VG, Makarava N, Baskakov IV. 2010 he α-Helical C-Terminal Domain of Full-Length Recombinant PrP Converts to an In-Register Parallel β-Sheet Structure in PrP Fibrils: Evidence from Solid State Nuclear Magnetic Resonance, Biochemistry, V.49, p9488-9497.
Lee, Y. J., Baskakov, I.V. 2010 Treatment with normal prion protein delays differentiation and helps to maintain high proliferation activity in human embryonic stem cells. J. Neurochem. V114(2), p.362-373. PMID: 20089130
Ostapchenko, V., Sawaya, M., Makarava, M., Savtchenko, R., Nilsson, P.R., Eisenberg, D., Baskakov, I.V., 2010 Two amyloid states of the prion protein display significantly different folding patterns, J.Mol.Biol. V. 400, p908-921.
Makarava, N., Kovacs, G.G., Bocharova, O., Savtchenko, R., Alexeeva , I., Budka, H., Rohwer , R.G., Baskakov, I.V. 2010 Recombinant prion protein induces a new transmissible prion disease in wild type animals, Acta Neuropathol. V. 119, p177-178; PMID: 20052481.
Colby, D.W., Wain, R., Baskakov, I.V., Legname, G., Palmer, C.G., Nguyen, H.O.B., Lemus, A., Cohen, F., DeArmond, S., Prusiner, S.B. 2010, Protease-sensitive synthetic prions, PLoS Pathog. V. 6, e1000736.34.
Makarava, M., Ostapchenko, V., Savtchenko, R., Baskakov, I.V., 2009, Conformational switching within individual amyloid fibrils. J.Biol.Chem. V. 284, p. 14386-14395. PMID: 19329794
Colby, D., Giles, K., Legname, G., Wille, H., Baskakov, I.V., DeArmond, S., Prusiner, S.B. 2009, Design and construction of diverse mammalian prion strains. Proc. Natl. Acad. Sci. USA, V. 106, p.20417-20422.
Sun,Y., Makarava,N., Lee, C.I., Laksanalamai, P., Robb, F.T., and Baskakov,I.V. 2008 Conformational stability of PrP Amyloid Fibrils Controls Their Smallest Possible Fragment Size. J.Mol.Biol. V. 376, p. 1155-1167
Makarava, N., Baskakov, I.V. 2008 The same primary structure of the prion protein yields two distinct self-propagating states J.Biol.Chem. V. 283, p. 15988-15996.
Makarava, N., Baskakov, I.V. 2008 Expression and purification of full-length recombinant PrP of high purity. Methods Mol Biol. V.459, p.131-43.
Breydo, L., Makarava, N., Baskakov, I.V. 2008 Methods for conversion of prion protein into amyloid fibrils. Methods Mol Biol. V. 459, p.105-115.
Ostapchenko, V., Makarava, M., Savtchenko, R., Baskakov, I.V., 2008, The polybasic N-terminal region of the prion protein controls the physical properties of both the cellular and fibrillar forms of PrP, J.Mol.Biol. V. 383, p.1210-1224
Breydo, L., Sun, Y., Makarava, N., Lee, C.-I., Novitskaia, V., Bocharova, O.V., Kao, J., Baskakov, I.V. 2007 Nonpolar substitution at C-terminus of the prion protein, a mimic of GPI anchor, partially impairs amyloid fibrils formation, Biochemistry, V. 46(3), p.852-861
Sun,Y., Breydo,L., Makarava,N., Yang,Q., Bocharova,O.V., and Baskakov,I.V. 2007 Site-specific conformational studies of prion protein (PrP) amyloid fibrils revealed two cooperative folding domains within amyloid structure. J.Biol.Chem. V. 282(12), p. 9090-9097
Novitskaia, V., Makarava, N., Sylvester, I., Bronstein, I. Baskakov, I.V. 2007 Amyloid fibrils of mammalian prion protein induce axonal degeneration in NTERA2-derived terminally differentiated neurons. J Neurochem. V.102, p. 398-407.
Lee, C.I., Yang, Q., Perrier, V., Baskakov, I.V. 2007 The dominant-negative effect of the Q218K variant of the prion protein does not require protein X. Protein Science. 16(10), p. 2166-2173.
Makarava, N., Lee, C.I., Ostapchenko, V.G., Baskakov, I.V. 2007 Highly promiscuous nature of prion polymerization. J.Biol.Chem. V. 282, p. 36704-36713.
Bocharova, O.V., Makarava, N., Breydo, L., Anderson, M., Salnikov, V.V, Baskakov, I.V. 2006 Annealing PrP amyloid fibrils at high temperature results in transition from proteinase K resistant to proteinase K sensitive form. J. Biol. Chem., v. 281, p.2373-2379.
Anderson, M., Bocharova, O.V., Makarava, N., Breydo, L., Salnikov, V.V, Baskakov, I.V. 2006 High Polymorphism and Ultrastructural Organization of Prion Protein Amyloid Fibrils: An Insight from High Resolution Atomic Force Microscopy, J.Mol.Biol. V. 358, p. 580-596.
Makarava, N., Bocharova, O.V., Salnikov, V.V, Breydo, L., Anderson, M., Baskakov, I.V. 2006 Dichotomous versus palm-type mechanisms of lateral assembly of amyloid fibrils, Protein Science, V. 15(2), p. 1334-1341
Novitskaia, V., Bocharova, O.V., Bronstein, I. Baskakov, I.V. 2006 Amyloid fibrils of mammalian prion protein are highly toxic to cultured cells and primary neurons, J.Biol.Chem. V. 281, p. 13828-13836.
Novitskaia, V., Makarava, M., Bellon A., Bocharova, O.V., Bronstein, I. Williamson, A., Baskakov, I.V. 2006 Probing the conformation of the prion protein within a single amyloid fibrils using a novel immunoconformational assay, J.Biol.Chem. V. 281, p. 15536-15545. Cited 36 times.
Baskakov, I.V., Bocharova, O.V., 2005, In vitro conversion of mammalian prion protein into amyloid fibrils displays unusual features. Biochemistry, v.44, p. 2339-2348.
Bocharova, O.V., Breydo, L., Salnikov, V.V., Gill, A.C., Baskakov, I.V. 2005, Synthetic prions generated in vitro are similar to a newly identified subpopulation of PrPSc from sporadic Creutzfeldt-Jakob Disease. Protein Science, v.14(5), p.1222-1232. 29.
Makarava, N., Parfenov, A., Baskakov, I.V., 2005 Water-soluble hybrid nanoclusters with extra bright and photostable emissions: new tool for biological imaging, Biophys. J. v. 89, p. 572-580
Bocharova, O.V., Breydo, L., Salnikov, V.V., Baskakov, I.V. 2005, Copper(II) inhibits in vitro conversion of prion protein into amyloid fibrils. Biochemistry, v. 44, p.6776-6787.
Breydo, L., Bocharova, O.V., Makarava, N., Salnikov, V.V., Anderson, M., Baskakov, I.V. 2005 Methionine Oxidation Interferes with Conversion of the Prion Protein into the Fibrillar Proteinase K-Resistant Conformation, Biochemistry, v. 44, p. 15534-15543.
Legname,G.; Nguyen,H.-O.B., Baskakov,I.V.,. Cohen,F.E., DeArmond,S.J., Prusiner,S.B. 2005 Strain-specified characteristics of mouse synthetic prions. Proc. Natl. Acad. Sci. USA, v.102, p. 2168-2173.
Bocharova, O.V., Breydo, L., Parfenov, A, Salnikov, V.V., Baskakov, I.V., 2005 In vitro conversion of full-length mammalian prion protein produces amyloid form with physical properties of PrPSc. J. Mol. Biol. v.346, p 645-659
Baskakov, I.V 2004, Autocatalytic Conversion of Recombinant Prion Proteins Displays a Species Barrier. J. Biol. Chem., V. 279 (9) p. 7671-7677.
Legname,G.*; Baskakov,I.V.*; Nguyen,H.-O.B.; Riesner,D.; Cohen,F.E.; DeArmond,S.J.; Prusiner,S.B. 2004, Synthetic Mammalian Prions, Science, v.305, p. 673-676. (*equal contributions).
Bolen, D.W. Baskakov, I.V. 2001, The Osmophobic effect: Natural Selection of a Thermodynamic Force in Protein Folding, J. Mol. Biol. v.310. p.955-963. Cited > 300 times.
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