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Computational Investigation of Thiol-Based Redox Modifications in Proteins: Redox-Active Disulfides, Zn2+ Sites and Their Associations

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Computational Investigation of Thiol-Based Redox Modifications in Proteins: Redox-Active Disulfides, Zn2+ Sites and Their Associations THESIS SUBMITTED IN TOTAL FULFILLMENT OF THE REQUIREMENTS OF THE DEGREE OF DOCTOR OF PHILOSOPHY Computational investigation of thiol‐based redox modifications in proteins: redox‐active disulfides, 2+ Zn sites and their associations Application of tools of bioinformatics in health and disease Dhakshinari Vihara Kumari Hulugalle March 2013 Victor Chang Cardiac Research Institute School of Medical Sciences, Faculty of Medicine, University of New South Wales PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: HULUGALLE First name: DHAKSHINARI Other name/s: VIHARA KUMARI PhD Abbreviation for degree as given in the University calendar: School: SCHOOL OF MEDICAL SCIENCES Faculty: MEDICINE Title: Computational investigation of thiol-based redox modifications in proteins: redox-active disulfides, Zn2+ sites and their associations Abstract 350 words maximum: (PLEASE TYPE) Thiol based redox signalling is an emerging area of research in protein science. Reversible disulfide bonding and Zn2+ expulsion are two important but less explored oxidative thiol modifications associated with redox signalling. They have numerous implications in health and disease. Three computational methods have previously been developed to predict redox-active disulfides in proteins: redox pair protein (RP) method, ‘forbidden disulfides’ (FD) method and torsional energy (TE) method. These methods and other tools of bioinformatics are used in my study to investigate redox-active disulfides, Zn2+ sites and the association between FDs and Zn fingers in protein structures. The first objective of my study was to apply the RP method to predict novel proteins containing likely redox-active disulfides. Over 300 novel RP proteins were found during this study. Significant conformational changes associated with disulfide redox activity in RP protein structures were also identified. I accomplished another objective, to predict proteins with likely redox-active disulfides and thiols in M. tuberculosis and C. glutamicum by matching protein disulfide templates derived by the FD, RP and TE methods to the genomes of these organisms. Expulsion of Zn2+ from proteins following oxidation of ligating cysteine residues is an emerging area in oxidative stress response. Trends in the ligating residue combination patterns at redox-active and inert protein Zn2+ sites were successfully identified, to achieve the second objective of my study. The third objective was to identify specific types of FDs associated with Zn fingers. A novel type of FD motif called the anti-parallel hairpin-diagonal disulfide (aHDD) was discovered during the study. The presence of this motif and its variants in the structure is characteristic of different types of Zn fingers, suggesting a functional relationship. An aHDD motif based extension to a Zn finger classification system was also proposed in this study. I have also estimated around 81% of human Zn finger proteins to be associated with the aHDD motif, suggesting its likely importance in Zn2+ signalling. Finally, the above investigations are discussed and future directives are proposed to further enhance our knowledge of redox-active disulfides, Zn2+ sites and their associations in protein structures. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………… ……………………………………. ……….……………………...…….… Signature Witness Date The University recognizes that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS Originality Statement I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. Signed....................................... Date.......................................... COPYRIGHT STATEMENT I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorize University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation. Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format. Signed ……………………………………………........................... Date ……………………………………………........................... Table of Contents Abstract…………………………………………………………………………………………………………………. V Acknowledgements………………………………………………………………………………………………… VII Awards, Presentations and Publications arising from this thesis…………………………..... VIII List of Figures…………………………………………………………………………………………………………. X List of Tables………………………………………………………………………………………………………….. XIV Abbreviations…………………………………………………………………………………………………………. XVI Chapter 1 – Introduction……………………………………………………………………………………… 1 1.1 Introduction………………………………………………………………………………………………. 2 1.2 Oxidative thiol modifications in redox signalling……………………………………….. 3 1.3 The disulfide linkage…………………………………………………………………………………. 8 1.3.1 The disulfide linkage in proteins………………………………………………………… 8 1.3.2 The disulfide proteome – A historical perspective……………………………… 9 1.3.3 Structural classification of disulfide bonds…………………………………………. 12 1.3.4 Sub‐cellular location of disulfide bonded proteins……………………………… 13 1.3.5 Thiol‐disulfide exchange in proteins…………………………………………………… 14 1.4 Redox active disulfides……………………………………………………………………………… 15 1.4.1 Methods to identify redox active disulfides………………………………………… 15 1.4.2 Computational data mining techniques for the prediction of redox 18 active disulfides…………………………………………………………………………………. 1.4.3 High torsional energy disulfides…………………………………………………………. 19 1.4.4 Forbidden disulfides…………………………………………………………………………… 21 1.4.5 Redox pairs………………………………………………………………………………………… 25 1.4.6 Protein conformational changes associated with disulfide redox 25 activity………………………………………………………………………………………………. I 1.4.7 Association of Zn2+ sites and redox‐active disulfides………………………….. 26 1.5 Zn2+ in proteins………………………………………………………………………………………… 26 1.5.1 The metal ion Zn2+ in proteins……………………………………………………………… 26 1.5.2 Special features of Zn2+………………………………………………………………………… 27 1.5.3 Extent of Zn2+ in human genome………………………………………………………… 29 1.5.4 Role of Zn2+ in human physiology………………………………………………………… 29 1.5.5 Redox role of Zn2+ in human physiology ……………………………………………… 31 1.6 The association between Zn2+ and Cys……………………………………………………… 32 1.6.1 Zn2+‐Cys interaction……………………………………………………………………………… 32 1.6.2 Oxidative modification of the Zn2+‐Cys linkage in proteins……………………. 33 1.6.3 Zn2+‐Cys partnership in biological redox switches…………………………………. 35 1.7 Zn2+ sites in proteins…………………………………………………………………………………. 37 1.7.1 Zn2+ ‐coordination sites……………………………………………………………………….. 37 1.7.1.1 Structural Zn2+ sites……………………………………………………………………. 38 1.7.1.2 Catalytic Zn2+ sites……………………………………………………………………… 38 1.7.1.3 Co‐catalytic Zn2+ sites………………………………………………………………… 39 1.7.1.4 Protein interface Zn2+ sites………………………………………………………… 39 1.7.2 Coordination geometry at Zn2+ binding sites………………………………………. 39 1.7.3 Redox sensitivity of Zn2+ coordination sites………………………………………… 40 1.7.4 Zn fingers
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