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Understanding the molecular mechanism of activation of the proteostasis regulator PQM-1 during stress and aging.

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  • Full or part time
    Dr Patricija van Oosten-Hawle
    Dr Anastasia Zhuravleva
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

A major challenge in biology is to understand how cells protect the integrity of the cellular proteome in the face of stress and aging that results in protein misfolding diseases. To counteract cellular damage each cell has the ability to rapidly activate stress response pathways that induce the expression of protective components such as molecular chaperones. We have identified a novel component of the proteostasis network, a GATA transcription factor, that activates the expression of a specific set of chaperones and other components to protect from age-dependent protein misfolding diseases.

This project will take advantage of two major approaches: 1) modern structural biology and biophysics approaches (CD, SPR, Bio-NMR) to understand mechanistically how the GATA transcription factor becomes activated during temperature stress. We will determine the conformational changes that drive its interaction with regulatory proteins in a complex and with DNA. 2) The second major approach will be an in vivo approach, that uses C. elegans as a model system. This will allow us to monitor the intracellular dynamics of a fluorescently tagged version of the GATA transcription factor during stress and aging by utilizing next generation bio-imaging and cell biology approaches. C. elegans models for human neurodegenerative protein folding diseases such as Alzheimer’s or Huntington’s Disease will be used to determine the efficacy of modified versions of the novel proteostasis component against aging and disease.

The supervisory team will provide expertise in protein biochemistry, biophysics and structural biology (Dr. Zhuravleva) and C. elegans biology, cell biology, genetics and bio-imaging (Dr. van Oosten-Hawle).


Please see following links for more information:

http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=POH

https://www.vanoostenhawlelab.com/

Twitter: @HawleLab

http://www.fbs.leeds.ac.uk/staff/profile.php?un=fbspv

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.

There are 2 stages to the application process. Please see our website for more information: http://www.fbs.leeds.ac.uk/postgraduate/phdopportunities.php

References

VAN OOSTEN-HAWLE:
Daniel O’Brien* and van Oosten-Hawle,P. (2016). Regulation of cell nonautonomous proteostasis in metazoans. Essays in Biochemistry. 2016 Oct 15;60(2):133-142.
*post graduate co-author.

Tipping KW; van Oosten-Hawle P; Hewitt EW; Radford SE (2015). Amyloid fibres: inert end-stage aggregates or key players in disease? Trends in Biochemical Sciences, 2015. 40 (12):719-27

van Oosten-Hawle P, Morimoto RI. 2014. Organismal Proteostasis: role of cell nonautonomous regulation and intertissue stress signaling. Genes & Development. 2014 Jul 15; 28(14):1533-1543.

van Oosten-Hawle P, Porter RS, Morimoto RI. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153:1366-78

ZHURAVLEVA:
Wieteska, L., Shahidi, S., Zhuravleva A. (2017) Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation. eLife (In Press).

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

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

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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