Research Units
Structural Biology Unit
Laboratory 2
Protein complexes of diverse nature are the main subjects in our crystallographic projects. We aim to understand if the knowledge of structural principles of a biological intermolecular recognition can be exploited to control and pharmacologically modulate protein specificity. We focus our efforts on human neurodegenerative diseases, and currently study complexes with RNA, in project: "Structural Basis for Suppression of Human Trinucleotide Repeat Expansion Diseases (TREDs)" and complexes with glycolipids in project: " Molecular Basis for Manipulating the Selectivity of Glycolipid Transfer".
- Structural Basis for Suppression of Human Trinucleotide Repeat Expansion Diseases
- Molecular Basis for Manipulating the Selectivity of Glycolipid Transfer
Expanded tracts of repeated triplet sequences in DNA cause many muscle- and neurodegenerative diseases. Our central hypothesis is that the mechanism of pathogenesis involves a RNA interference pathway, which could be inhibited by means of a viral suppressor of RNA interference p19. The protein p19 is known to bind to small interfering RNAs (siRNAs) in a sequence non-specific manner. Our goal is to identify the p19 mutations, which make it disease-repeat specific. We intend to use the X-ray crystallographic approaches to elucidate the structural principles for manipulating the p19/siRNA binding specificity.
Membrane lipids are increasingly being recognized as regulators of numerous cellular processes. Much attention is focused on the mechanisms by which cells impose selectivity and directionality on lipid movement. Glycosphingolipids (GSLs), key regulators of cellular differentiation, growth, development, and apoptosis, are synthesized in the Golgi, and delivered to others membranes by both vesicular and non-vesicular mediated pathways. Glycolipid transfer proteins (GLTPs) are small, soluble, and ubiquitous proteins that selectively accelerate the intermembrane transfer of glycolipids. The preliminary structural insights suggest a strict specificity of GLTP for glycolipid, and a concerted sequence of events during GSL transfer to/from membranes. Our intention is ‘to evolve’ artificial GLTP species capable of distinguishing sugar headgroups and lipid chain structures.
- Dr Rhoderick E Brown (The Hormel Institute, Austin MN, USA).
- Dr Alexander Popov (ESRF, Grenoble, France).
- Dr Dinshaw J Patel (MSKCC, New York NY, USA).
Publications
Jevgenia Tamjar, Elizaveta Katorcha, Alexander Popov & Lucy Malinina; Structural dynamics of double-helical RNAs composed of CUG/CUG- and CUG/CGG-repeats. Journal of Biomolecular Structure and Dynamics 30, 5 505-523 (2012)
Samygina VR, Popov AN, Cabo-Bilbao A, Ochoa-Lizarralde B, Goni-de-Cerio F, Zhai X, Molotkovsky JG, Patel DJ, Brown RE, Malinina L.; Enhanced Selectivity for Sulfatide by Engineered Human Glycolipid Transfer Protein. Structure 19, 11 1644-54 (2011)
Teplova M, Malinina L, Darnell JC, Song J, Lu M, Abagyan R, Musunuru K, Teplov A, Burley SK, Darnell RB, Patel DJ.; Protein-RNA and Protein-Protein Recognition by Dual KH1/2 Domains of the Neuronal Splicing Factor Nova-1.. Structure 19, 7 930-944 (2011)
Kenoth R, Kamlekar RK, Simanshu DK, Gao Y, Malinina L, Prendergast FG, Molotkovsky JG, Patel DJ, Venyaminov SY, Brown RE. ; Conformational Folding and Stability of the HET-C2 Glycolipid Transfer Protein Fold: Does a Molten Globule-like State Regulate Activity?. Biochemistry 50, 23 5163-5171 (2011)
Carton I, Malinina L, Richter RP; Dynamic modulation of the glycosphingolipid content in supported lipid bilayers by glycolipid transfer protein . Biophys. J. 99, 2947-2956 (2010)
Rechkoblit O, Kolbanovskiy A, Malinina L, Geacintov NE, Broyde S, Patel DJ; Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4. Nat Struct Mol Biol. 17, 3 379-88 (2010)
Kenoth R, Simanshu DK, Kamlekar RK, Pike HM, Molotkovsky JG, Benson LM, Bergen HR 3rd, Prendergast FG, Malinina L, Venyaminov SY, Patel DJ, Brown RE; Structural determination and tryptophan fluorescence of heterokaryon incompatibility C2 protein (HET-C2), a fungal glycolipid transfer protein (GLTP), provide novel insights into glycolipid specificity and membrane interaction by the GLTP-fold. J Biol Chem. 285, 17 13066-13078 (2010)
Kamlekar RK, Gao Y, Kenoth R, Molotkovsky JG, Prendergast FG, Malinina L, Patel DJ, Wessels WS, Venyaminov SY, Brown RE; Human GLTP: Three distinct functions for the three tryptophans in a novel peripheral amphitropic fold. Biophys. J. 99, 2626-2635 (2010)
Rechkoblit O, Malinina L, Cheng Y, Geacintov NE, Broyde S, Patel DJ; Impact of conformational heterogeneity of OxoG lesions and their pairing partners on bypass fidelity by Y family polymerases. Structure 17, 5 725-36 (2009)
Zhai X, Malakhova ML, Pike HM, Benson LM, Bergen HR 3rd, Sugár IP, Malinina L, Patel DJ, Brown RE.; Glycolipid acquisition by human glycolipid transfer protein dramatically alters intrinsic tryptophan fluorescence: insights into glycolipid binding affinity. J Biol Chem. 284, 20 13620-8 (2009)