Faculty of Biological Sciences

Dr Anastasia Zhuravleva

Lecturer in Molecular and Cellular Biology
School of Molecular and Cellular Biology

Contact:  Miall 6.01, +44(0) 113 34 37750, email address for  

You can read more about Dr Zhuravleva's interests here:
http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=AZ

Research Interests

Molecular mechanisms of the protein quality control network

We currently have a post-doctoral position available: https://jobs.leeds.ac.uk/Vacancy.aspx?id=2139&forced=1

Nearly one-third of all newly synthesized proteins (including the majority of secreted and membrane proteins) are first segregated in the endoplasmic reticulum (ER) – the organelle responsible for proper folding and posttranslational modifications for these proteins. Imbalances in ER folding homeostasis results in many pathological processes, including neurodegenerative diseases, diabetes and cancer. A conserved protein quality control (PQC) network of ER molecular chaperones and degradation enzymes controls correct protein folding and the disaggregation/clearance of misfolding proteins. To this end, a key player in the PQC network – an ER Hsp70 molecular chaperone called BiP – is one of the most attractive pharmaceutical targets for tackling protein-folding diseases.    

Similar to other Hsp70 chaperones, many BiP functions rely on repeated binding and releasing of unfolded or misfolded protein substrates. These events are regulated by conformational changes in the protein that occur upon ATP binding and hydrolysis. An understanding of the molecular details and mechanisms that underlie BiP functions is essential for designing BiP-targeting drugs and will provide in-depth insights into BiP allostery and contribute to our fundamental understanding of protein quality control mechanisms. The objectives of this PhD project will be to:      

1) Elucidate the relationship between BiP conformational changes along its allosteric cycle and BiP functions (ATPase hydrolysis and binding to unfolded/misfolded substrates) 

2) Identify BiP ‘hot spots’ – protein sites that allosterically control and fine-tune BiP conformation and thus, adjust its function

3) Explore molecular mechanisms of BiP interactions within the PQC network and characterize how these interactions affect BiP activity and function

4) Characterize BiP interactions with its natural substrates and understand the molecular mechanism that allows BiP to prevent protein aggregation and misfolding

The project utilizes a multidisciplinary cutting-edge methodology including recombinant expression, mutagenesis and protein construct design; biomolecular NMR, computer modeling and molecular dynamics simulations, biophysical characterization and screening of ligand binding and aggregation (ITC, fluorescence, MS).

 

Faculty Research and Innovation



Studentship information

Undergraduate project topics:

  • Molecular mechanisms of protein misfolding diseases
  • Structural and mechanistic characterisation of the ER protein quality control network

Postgraduate studentship areas:

  • NMR screening of small molecule inhibitors targeting endonuclease activity of an ER stress sensor Ire1 (with Dr Beining Chen, Sheffield; The project is a part of the Studentship Network "Structural and Mechanistic Biology at the RNA/Ligand Interface":http://www.whiterose.ac.uk/studentships/structural-and-mechanistic-biology-at-the-rnaligand-interface/ )
  • Molecular mechanisms of the action of the ER molecular chaperone BIP
  • New approaches to combatting amyloid disease from mechanistic insights (with Prof Radford)

See also:

Modules managed

BIOC2303 - Intermediate Biochemistry: Skills

Modules taught

BIOC2302 - Intermediate Biochemistry: Practicals
BIOC2303 - Intermediate Biochemistry: Skills
BIOC2303/BIOL2303 - Intermediate MCB Skills

Centre membership: The Astbury Centre for Structural Molecular Biology

Group Leader Dr Anastasia Zhuravleva  (Lecturer in Molecular and Cellular Biology)

Molecular mechanisms of the protein quality control network 

Postgraduates

Sam Dawes (Primary supervisor) 100% FTE
Nicholas Hurst (Primary supervisor) 60% FTE
Lucy Barber (Co-supervisor) 50% FTE
Lauren Branfield (Co-supervisor) 33% FTE
Outi Kamarainen (Co-supervisor) 45% FTE

Zhuravleva A, Korzhnev DM Protein folding by NMR Progress in Nuclear Magnetic Resonance Spectroscopy 100 52-77, 2017
DOI:10.1016/j.pnmrs.2016.10.002
View abstract

Tomlinson JH, Thompson GS, Kalverda AP, Zhuravleva A, O'Neill AJ A target-protection mechanism of antibiotic resistance at atomic resolution: Insights into FusB-type fusidic acid resistance Scientific Reports 6 -, 2016
DOI:10.1038/srep19524
View abstract

Zhuravleva A, Gierasch LM Substrate-binding domain conformational dynamics mediate Hsp70 allostery Proceedings of the National Academy of Sciences of the United States of America 112 E2865-E2873, 2015
DOI:10.1073/pnas.1506692112
View abstract

Zhuravleva A, Radford SE How tric folds tricky proteins. Cell 159 1251-1252, 2014
DOI:10.1016/j.cell.2014.11.029
View abstract

Ferrolino MC, Zhuravleva A, Budyak IL, Krishnan B, Gierasch LM A delicate balance between functionally required flexibility and aggregation risk in aβ-rich protein. Biochemistry 52 8843-8854, 2013
DOI:10.1021/bi4013462
View abstract

Budyak IL, Zhuravleva A, Gierasch LM The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization ofβ-Sheets. J Mol Biol 425 3522-3535, 2013
DOI:10.1016/j.jmb.2013.06.030
View abstract

Shenkarev ZO, Paramonov AS, Lyukmanova EN, Gizatullina AK, Zhuravleva AV, Tagaev AA, Yakimenko ZA, Telezhinskaya IN, Kirpichnikov MP, Ovchinnikova TV, Arseniev AS Peptaibol antiamoebin I: Spatial structure, backbone dynamics, interaction with bicelles and lipid-protein nanodiscs, and pore formation in context of barrel-stave model Chemistry and Biodiversity 10 838-863, 2013
DOI:10.1002/cbdv.201200421
View abstract

Budyak IL, Krishnan B, Marcelino-Cruz AM, Ferrolino MC, Zhuravleva A, Gierasch LM Early folding events protect aggregation-prone regions of aβ-rich protein. Structure 21 476-485, 2013
DOI:10.1016/j.str.2013.01.013
View abstract

Zhuravleva A, Clerico EM, Gierasch LM An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151 1296-1307, 2012
DOI:10.1016/j.cell.2012.11.002
View abstract

Wang Q, Zhuravleva A, Gierasch LM Exploring weak, transient protein--protein interactions in crowded in vivo environments by in-cell nuclear magnetic resonance spectroscopy. Biochemistry 50 9225-9236, 2011
DOI:10.1021/bi201287e
View abstract

Zhuravleva A, Gierasch LM Allosteric signal transmission in the nucleotide-binding domain of 70-kDa heat shock protein (Hsp70) molecular chaperones. Proc Natl Acad Sci U S A 108 6987-6992, 2011
DOI:10.1073/pnas.1014448108
View abstract

Clerico EM, Zhuravleva A, Smock RG, Gierasch LM Segmental isotopic labeling of the Hsp70 molecular chaperone DnaK using expressed protein ligation. Biopolymers 94 742-752, 2010
DOI:10.1002/bip.21426
View abstract

Jaravine VA, Zhuravleva AV, Permi P, Ibraghimov I, Orekhov VY Hyperdimensional NMR spectroscopy with nonlinear sampling Journal of the American Chemical Society 130 3927-3936, 2008
DOI:10.1021/ja077282o
View abstract

Zhuravleva A, Orekhov VY Divided evolution: a scheme for suppression of line broadening induced by conformational exchange. J Am Chem Soc 130 3260-3261, 2008
DOI:10.1021/ja710056t

Chevelkov V, Zhuravleva AV, Xue Y, Reif B, Skrynnikov NR Combined analysis of 15N relaxation data from solid- and solution-state NMR spectroscopy Journal of the American Chemical Society 129 12594-12595, 2007
DOI:10.1021/ja073234s
View abstract

Zhuravleva A, Korzhnev DM, Nolde SB, Kay LE, Arseniev AS, Billeter M, Orekhov VY Propagation of dynamic changes in barnase upon binding of barstar: an NMR and computational study. J Mol Biol 367 1079-1092, 2007
DOI:10.1016/j.jmb.2007.01.051
View abstract

Sigalov AB, Zhuravleva AV, Orekhov VY Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form Biochimie 89 419-421, 2007
DOI:10.1016/j.biochi.2006.11.003
View abstract

Zhuravleva AV, Korzhnev DM, Kupce E, Arseniev AS, Billeter M, Orekhov VY Gated electron transfers and electron pathways in azurin: A NMR dynamic study at multiple fields and temperatures Journal of Molecular Biology 342 1599-1611, 2004
DOI:10.1016/j.jmb.2004.08.001
View abstract

Korzhnev DM, Bocharov EV, Zhuravlyova AV, Tischenko EV, Reibarkh MY, Ermolyuk YS, Schulga AA, Kirpichnikov MP, Billeter M, Arseniev AS <sup>1</sup>H,<sup>13</sup>C and<sup>15</sup>N resonance assignment for barnase Applied Magnetic Resonance 21 195-201, 2001
View abstract

Korzhnev DM, Bocharov EV, Zhuravlyova AV, Orekhov VY, Ovchinnikova TV, Billeter M, Arseniev AS Backbone dynamics of the channel-forming antibiotic zervamicin IIB studied by 15N NMR relaxation. FEBS Lett 495 52-55, 2001
View abstract

Vyssokikh MY, Goncharova NY, Zhuravlyova AV, Zorova LD, Kirichenko VV, Krasnikov BF, Kuzminova AE, Melikov KC, Melik-Nubarov NS, Samsonov AV, Belousov VV, Prischepova AE, Zorov DB Proteinaceous complexes from mitochondrial contact sites Biochemistry (Moscow) 64 390-398, 1999
View abstract

Vyssokikh MY, Goncharova NY, Zhuravlyova AV, Zorova LD, Kirichenko VV, Krasnikov BF, Kuzminova AE, Melikov KC, Melik-Nubarov NS, Samsonov AV, Belousov VV, Prischepova AE, Zorov DB Proteinaceous complexes from mitochondrial contact sites Biokhimiya 64 466-475, 1999
View abstract

Kuzminova AE, Zhuravlyova AV, Vyssokikh MYu, Zorova LD, Krasnikov BF, Zorov DB The permeability transition pore induced under anaerobic conditions in mitochondria energized with ATP. FEBS Lett 434 313-316, 1998
View abstract

Wieteska L, Shahidi S, Zhuravleva A Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation eLife -,