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Dr. Jody Mason
Research Details
We focus on the coiled coil system as it is simplistic, but highly
specific, being ubiquitous and important for many biological processes;
found 3-5% of the entire coding sequence it serves in transcriptional
control, muscle contraction, viral infection, cell signaling, molecular
chaperones, and fertilization, and is therefore the ideal test-bed on which
to test specificity. In addition, many of the rules arising from
interactions involving coiled coils are also applicable to other
protein-protein interactions. Coiled coils are characterized by a regular
repeating unit of seven amino acids (a heptad repeat) labelled a-g, with a
specific pattern of hydrophobic and hydrophilic residues.
The Jun and Fos coiled coil proteins from the mammalian transcription
factor activator protein-1 (AP-1) consist of a variety of cellular
homologues which are expressed in different tissues, leading to increased
levels of proliferation, invasion, and metastasis when upregulated. A
variety of oncogenic signaling pathways converge on AP-1 which ultimately
controls gene expression patterns. Accordingly, designing inhibitors to
sequester specific AP-1 components is of great interest for analytical as
well as therapeutic purposes. Such inhibitors are derived using a
semirational library approach combined with a protein fragment
complementation assay (PCA) for selecting librarymembers with highest
affinity. In PCA, one half of murine dihydrofolate reductase (mDHFR) is
genetically fused to the target, and the second half of mDHFR is fused to
the protein library. Only library members binding to the peptide target will
bring the two halves of DHFR together, render the enzyme active, and result
in a bacterial colony under selective conditions. Subsequent growth
competitions under selective conditions enrich the “winning” peptides, which
can then be characterised.
To increase interaction specificity, we added homologous competitors to
the PCA system. In this new system, library members must not only bind their
target (positive design) but also bind it with higher affinity than the
competitor (competition) and also evade binding to the competitor itself
(negative design). Consequently, we term this a “competitive and negative
design initiative” (CANDI). To demonstrate in vivo negative design, we
combined CANDI with PCA selection, where non-DHFR-fragment fusions of cFos
or cJun are used to compete with libraries, for an interaction with Jun and
Fos target peptides.
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Career Resumé
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2007-present –
Lecturer, Department of Biological Sciences, University of Essex
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2003-2007 –
Postdoctoral Research Fellow, Department of Biology III, Albert-Ludwigs
University of Freiburg, Freiburg im Breisgau, Germany.
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2001-2003 -
Postdoctoral Research Associate, Department of Biomolecular Sciences, UMIST
(University of Manchester).
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2000-2001 –
Temporary Postdoctoral Researcher, Department of Biochemistry, University of
Bristol.
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1997-2000 - Ph.D.
in Protein folding. Department of Biochemistry, University of Bristol.
(Supervisor Prof. Tony Clarke).
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1994-1997 - B.Sc.
(Hons) Biochemistry. University of Bristol.
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Patents:
Patent #WO2006087550, 2006-08-24, Doig A.J. (GB); Stott K. (GB); Mason J.M.
(GB); Kokkoni N. (GB); Amijee H. (GB); Treheren J.M. (GB); Scopes D.I.C.
(GB), "Amyloid-binding peptides, analogues and uses thereof"
List of Recent Publications
(see Current
Departmental Publications)
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Mason, J.M. Electrostatic Contacts in the
Activator Protein-1 Coiled Coil Enhance Stability Predominantly by
Decreasing the Unfolding Rate. FEBS. J. 276, 7305-7318 (2009).
-
Mason, J. M., Hagemann, U. B., and Arndt, K. M. (2009) Role of Hydrophobic
and Electrostatic Interactions in Coiled Coil Stability and Specificity.
Biochemistry, 48, 10380-10388.
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Mason, J.M., Müller, K.M. & Arndt, K.M.,
Peptides Tailored to Interfere with Protein Interaction and Function.
Chemistry Today. Vol 27(2), 47-50, (2009).
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Mason, J.M., Mueller,
K.M., and Arndt, K.M., iPEP – Peptides Designed and Selected for
Interfering with Protein Interaction and Function. Biochem. Soc. Trans.,
36, 1442-1447 (2008).
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Hagemann, U.B., Mason, J.M., Müller,
K.M. and Arndt, K.M., Selectional and mutational scope of peptides
sequestering the Jun-Fos coiled-coil domain, J. Mol. Biol.
381, 73-88 (2008).
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Willemsen T, Hagemann U.B.,
Jouaux E.M., Stebel S.C., Mason J.M., Müller K.M., and Arndt K.M.,
Protein Engineering. Book Chapter in ‘Molecular Biomethods Handbook’,
2nd Edition, Eds John M Walker and Ralph Rapley (2008).
-
Mason, J.M.,
Hagemann, U., Arndt, K.M., Improved stability of the Jun−Fos Activator
Protein-1 coiled coil motif: A stopped-flow circular dichroism kinetic
analysis J. Biol. Chem. 282, 23015-23024 (2007).
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Mason, J.M., Müller,
K.M., and Arndt. K.M., Positive Aspects of Negative Protein Design:
Simultaneous Selection of Specificity and Stability. Biochemistry,
46, 4804-4814 (2007).
-
Mason, J.M., Müller,
K.M., and Arndt K.M., Considerations in the Design and Optimization of
Coiled coil Structures. Methods. Mol. Biol., 352, 35-70 (2007).
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Hecky, J., Mason, J.M., Arndt, K.M., and Müller, K.M., A General Method of
Terminal Truncation, Evolution, and Re-Elongation to Generate Enzymes of
Enhanced Stability. Methods. Mol. Biol., 352, 275-304 (2007).
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Mason, J.M., Müller,
K.M., Schmitz, M.A., and Arndt, K.M., Semirational Design of Jun-Fos
Coiled coils with Increased Affinity: Universal Implications in Leucine
zipper Prediction and Design. P.N.A.S. 103, 8989-8994, (2006).
Supporting
Information.
-
Kokkoni, N., Stott,
K., Amijee, H., Mason, J.M., and Doig, A.J., N-Methylated Peptide
Inhibitors of beta-Amyloid Aggreggation and Toxicity. Optimisation of
Inhibitor Structure. Biochemistry, 45, 9906-9918, (2006).
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Compton, E.L.R.,
Farmer, N.A., Lorch, M., Mason, J.M., Moreton, K.M., and Booth, P.J.,
Kinetics of an Individual Transmembrane Helix during Bacteriorhodopsin
Folding, J. Mol. Biol. 357, 325-38, (2006).
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Mason, J.M., Cliff
M.J., Sessions, R.B., and Clarke, A.R., Low-energy pathways and non-native
interactions: The influence of artificial disulfide bridges on the
mechanism of folding J.Biol.Chem. 280, 40494-40499 (2005).
-
Mason, J.M., and
Arndt K.M., Coiled coils: stability, specificity, and biological
implications. Chembiochem., 5, 170-6, (2004).
-
Mason J.M., Kokkoni
N., Stott K., and Doig A.J., Design strategies for anti-amyloid agents.
Curr. Op. Struct. Biol., 13, 526-32, (2003).
-
Mason, J.M., Gibbs,
N., Sessions, R.B., and Clarke A.R., The Influence of Intramolecular
Bridges on the Dynamics of a Protein Folding Reaction. Biochemistry,
40, 12093-12099, (2002).
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Lorch, M., Mason,
J.M., and Clarke, A.R., Effects of Mutations on the Thermodynamics of a
Protein Folding Reaction: Implications for the Mechanism of Formation of
Intermediate and transition States. Biochemistry, 39, 3480-3485,
(2000).
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Lorch, M., Mason,
J.M., Clarke, A.R., and Parker, M.J., Effects of Core Mutations on the
Folding of a β-sheet Protein:
Implications for Backbone Organisation in the I-state Biochemistry,
38, 1377-1385, (1999).
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Funding
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Sept 2007. New Lecturer
Start-up Fund, Essex University, £10,000
-
Oct 2007. Essex University
Departmental Research Fund, £2,627
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Nov 2007. Royal Society
Conference Grant, £1,220
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March 2008. Essex University
Departmental Research Fund, £1,938
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March 2008. Royal Society
Research Grant, £12,508
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Sept 2008. Alzheimer’s
Research Trust Pilot Project, £27,462
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Jan 2010, Research into
Ageing New Investigator Award, £43,552
Contact address
Department of Biological Sciences
University of Essex
Wivenhoe Park
Colchester
CO4 3SQ
UK tel. +44 (0)1206 873010
fax. +44 (0)1206 872592
email : prefix the name 'jmason' to the '@essex.ac.uk' stem
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