... understanding life in molecular detail

Dr Anastasia Zhuravleva

Protein quality control, molecular chaperones, stress response, NMR

Study and manipulation of protein homeostasis and the stress response raises the possibility of altering many pathological processes, including neurodegenerative diseases, diabetes and cancer. Our research deals with understanding the molecular mechanisms of stress responses in the endoplasmic reticulum (ER) and is focused on two central players in the ER homeostasis network, a molecular chaperone BIP and ER stress sensor IRE1. To tackle these multicomponent and dynamic systems, we use multidisciplinary approaches that combine modern structural biology techniques, such as NMR, structural prediction, X-ray, and cryo-EM.

Current major projects include:
  • Molecular mechanisms of stress responses
  • The ER protein quality control and Hsp70 chaperone, BiP
  • ER stress sensor IRE1
  • The relationship between protein structure, dynamics and function
  • Bio-NMR techniques for dynamic multicomponent systems

Folding of many secreted and membrane proteins in the endoplasmic reticulum (ER) is controlled by a conserved protein quality control (PQC) network of molecular chaperones and degradation enzymes ensuring correct folding or degradation. Imbalances in such protein homeostasis occur in many pathological processes, including neurodegenerative diseases, diabetes and cancer. Thus, an understanding of PQR is a fundamental question in biology and also offers future opportunities to intervene in pathological processes. An ER Hsp70 molecular chaperone called BiP is a key player in the ER quality control network and thus, one of the most attractive pharmaceutical targets for tackling protein-folding diseases. Understanding BiP functions, its structural features and its communication within the PQC network are key, yet unresolved challenges, and the target of my research programme.


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. Using solution NMR, we examined these ligand-driven structural changes and conformational flexibility in E. coli Hsp70, DnaK and elucidated a detailed mechanism by which an allosteric signal was transferred between its two domains: substrate-binding and nucleotide-binding (Cell 2012 and PNAS 2011).


Using these results as a starting point, we intend to examine functional, structural and thermodynamic features of ER Hsp70, BiP. We use a ‘divide-and-conquer’ approach that combines state-of-the-art multi-dimensional solution NMR, including methyl NMR and relaxation dispersion experiments, construct design and computational structural prediction algorithms to characterize this challenging multicomponent system, particularly to understand the unique features of the BiP conformational landscape; depict its differences and similarities with other members of the Hsp70 family; identify key allosteric residues (or ‘hotspots’) in the BiP molecule responsible for protein conformational changes; and elucidate the interdependent balance of BiP interactions with its co-chaperones, substrates and other members of the PQC network.

Detailed research programme                  Close ▲

Lecturer (Leeds) 2013 - present

Postdoctoral Fellow (Purdue University) 2006-2007
Postdoctoral Research Associate (University of Massachusetts at Amhers
Lecturer (Leeds) 2013-present

LIGHT 7.15a
School of Molecular and Cellular Biology

Selected Publications

  1. Zhuravleva*, A.; Gierasch*, L.M. (2015). Substrate-binding domain conformational dynamics mediate Hsp70 allostery. Proc Natl Acad Sci USA 112, E2865-E2873 (*corresponding authors)

  2. Tomlinson JH, Thompson GS, Kalverda AP, Zhuravleva A, O'Neill AJ. (2016) A target-protection mechanism of antibiotic resistance at atomic resolution: insights into FusB-type fusidic acid resistance. Scientific Reports 6, Article number: 19524

  3. Zhuravleva A*. & Radford SE* (2014). How TriC Folds Tricky Proteins. Cell. 159(6):1251-2. (*corresponding authors)

  4. Zhuravleva, A., Clérico, E. M., and Gierasch, L. M. An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151, 1296-1307, 2012