Research Overview
Neurodegenerative Diseases and Protein Aggregation
More than 15 severe diseases that lead to degeneration of human brain or other nervous tissue are caused by accumulation of misfolded proteins. The normal folding of the proteins is replaced by an abnormal form which is called the amyloid form. A detailed molecular understanding of how these abnormal forms occur, and how they are propagated, has important implications for medicine.
Prions
One of the most remarkable kinds of amyloid disease is caused by prions. What is unusual is that these diseases are inherited not by exposure to cells, DNA or RNA, but rather by the presence
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Research Description
Research Specialties: Prion Proteins, Protein Folding, Thermodynamics
With many putative rules that govern protein folding having been discovered, novel exciting directions are emerging from particular problems of neurodegenerative diseases. More than 15 severe maladies including prion, Alzheimer's, and Parkinson's diseases have been linked to specific protein aggregation. A common feature among all of these 'conformational' disorders is the conversion of a normal isoform of a protein into a specific -sheet rich polymeric amyloid form. Recent studies have demonstrated that a broad variety of proteins unrelated to any known conformational disease can adopt -sheet rich amyloid forms in vitro and in vivo. The fundamental questions are: how general the phenomenon of amyloidosis is (Figure 1) ; and if the amyloidosis is indeed more general than we thought before, what strategies presumably have evolved in nature to prevent amyloidosis?
Research in my lab is focused on the molecular mechanism of the conformational transitions of the prion and non-prion proteins and address basic issues of protein folding...
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Representative Publications
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. PMID:
18206163
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. PMID: 18400757
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. PMID: 18576153
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. PMID: 18576151
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. PMID:
18789949
Makarava, M., Ostapchenko, V.,
Savtchenko, R., Baskakov, I.V.,
Conformational switching within individual amyloid fibrils. 2009 submitted to J.Biol.Chem.
PMID: 19329794
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