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Structural and dynamic analysis of human glutaredoxin 3
Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Human glutaredoxin (Grx3) is an essential protein associated with biological functions including embryonic development and immune response, and is involved in human disease such as lung, colon cancer and cardiovascular disorder. Grx3 can harbour a [2Fe-2S]2+ cluster and is most likely involved in oxidative stress response. Grx3 consists of an N-terminal thioredoxin-like domain and two additional monothiol glutaredoxin domains, and is thus classified as a multidomain monothiol glutaredoxin. The Grx3 thioredoxin domain lacks both a characteristic active-site and catalytic activity, but is still essential in the yeast homologue and presumably functions together with its monothiol glutaredoxin domains. We have characterised the structures of the two Nterminal domains in Grx3, which have thioredoxin and glutaredoxin folds. We have analysed their dynamic and structural interdependence by analysing NMR relaxation data together with chemical shift changes between isolated and covalently linked domains. We find that although the two domains show interdomain mobility around a semi-flexible linker, there are indications for a preferred interaction surface between the two domains. Millisecond internal dynamics in a suggested ligand binding site in the isolated thioredoxin domain is dampened in the domain pair, suggesting that the two domains mutually affect each other on a profound level. Our results present a platform for further detailed studies of multidomain thioredoxin-glutaredoxin containing proteins, and their function in human cells.

National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70834OAI: oai:DiVA.org:liu-70834DiVA: diva2:441977
Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2011-09-20Bibliographically approved
In thesis
1. Protein Structure and Interaction in Health and Disease
Open this publication in new window or tab >>Protein Structure and Interaction in Health and Disease
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on protein structure, dynamics and interaction and their relation to human disease. In particular, the biophysical and structural properties of both well-ordered and partially disordered proteins are studied using a range of biophysical techniques such as circular dichroism spectroscopy, fluorescence spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy. Pseudomonas aeruginosa is a human pathogen due to its multidrug resistance (MDR) caused by overexpression of efflux pump systems. This thesis describes how MDR mutations within the MexR repressor of the MexAB-OprM system reduce the DNA affinity by altering its stability with maintained structure. The oncogenic protein c-Myc is involved in many essential biological functions such as cell proliferation, differentiation and apoptosis and is also highly associated with several forms of human cancers, and where the N-terminal domain is regulated by a plethora of protein interactions. In this thesis the intrinsically disordered N-terminal part of c-Myc and its interactions with the proteins Bin1 and TBP are described. Myc binds Bin1 with maintained disorder in a multivalent manner, which may explain why the onco-protein can interact with such a wide range of binding partners. A similarly dynamic interaction is observed for Myc with the TATA-binding protein (TBP). The essential human multidomain glutaredoxin Grx3 is associated with several biological functions such as redox signaling, proliferation and signal transduction. We have solved the structure and analyzed the dynamic properties in the ps-ns and ms time scale for the two N-terminal domains, providing a platform for further analysis of the Grx3 protein and its interactions. Taken together, this thesis emphasizes the importance of joint structural, biophysical and dynamic studies to better understand protein function in health and disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 67 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1394
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-70837 (URN)978-91-7393-077-2 (ISBN)
Public defence
2011-10-07, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 14:00 (Swedish)
Opponent
Supervisors
Available from: 2011-09-20 Created: 2011-09-20 Last updated: 2011-09-20Bibliographically approved

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Andrésen, CeciliaSunnerhagen, MariaLundström, Patrik

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