Phil Williamson and Group

Overview


PhilWilliamson Phil Williamson

 p.t.williamson@soton.ac.uk

Molecular interactions in biological membranes

Biological membranes are ubiquitous in nature and play a vital role in defining the interface of the cell with its environment and its intracellular compartmentalisation. In order to facilitate the transfer of information and materials across these barriers cells have evolved families of integral membrane proteins. The goal of our research is to understand the function of these proteins in their native lipid environment and for this purpose; we are developing solid-state NMR techniques which enable us to probe the structure and dynamics of these systems at an atomic level. In conjunction with other biophysical techniques, this method allows us to characterise how membrane proteins interact with other proteins, the surrounding lipids and other small molecules and to determine how these interactions modulate their function.

 

Research


Molecular interactions in biological membranes

Biological membranes are ubiquitous in nature and play a vital role in defining the interface of the cell with its environment and its intracellular compartmentalisation. In order to facilitate the transfer of information and materials across these barriers cells have evolved families of integral membrane proteins. The goal of our research is to understand the function of these proteins in their native lipid environment and for this purpose; we are developing solid-state NMR techniques which enable us to probe the structure and dynamics of these systems at an atomic level. In conjunction with other biophysical techniques, this method allows us to characterise how membrane proteins interact with other proteins, the surrounding lipids and other small molecules and to determine how these interactions modulate their function.

Recognition of small molecules by integral membrane receptors

The regulation of many integral membrane receptors is mediated through their interaction with small molecules. Our studies on the nicotinic acetylcholine receptor have enabled us to identify interactions involved in ligand binding and determine the conformation of the bound agonist, acetylcholine. Currently we are developing further solid-state NMR techniques to analyse how hydrophobic ligands such as anaesthetics may interact with the nicotinic acetylcholine receptor and aid in the rational development of pharmaceuticals against both this and other classes of membrane proteins.

Regulation of protein trafficking

The targeting of integral membrane proteins to the appropriate organelle or region at cell surface is vital to their function in eukaryotic cells. It is proposed that interactions between lipids and integral membrane proteins may play an important role in regulating this targeting process. Exploiting the potential of solid-state NMR techniques to study the structure of integral membrane proteins under near physiological conditions, we hope to be able to determine how bilayer composition and lateral phase separation may regulate the structure, oligomeric state and localization of integral membrane proteins and determine the role that this may play in regulating intracellular protein trafficking. These studies may provide molecular insights into a range of diseases linked to the mistrafficking of proteins.

Amyloidogenic diseases

A number of diseases important to modern society including Alzheimer’s, Parkinson’s and Huntington’s are characterised by the deposition of proteins as insoluble aggregates within the body. Solid-state NMR provides us with a unique opportunity to probe the structure of these aggregates at a molecular level. Currently we are employing solid-state NMR in conjunction with other biophysical techniques to characterise the structural transitions that result in the formation of these deposits. These studies are providing us with valuable insights into the onset and progression of these diseases and ascertaining the role other in-vivo factors may play in these diseases.

People

James Jarvis

Ibraheim Haies

Luke Evans

Michael Jolly

 

Publications


Friddin, Mark S., Smithers, Natalie P., Beaugrand, Maïwenn, Marcotte, Isabelle, Williamson, Philip T.F., Morgan, Hywel and de Planque, Maurits R.R. (2013) Single-channel electrophysiology of cell-free expressed ion channels by direct incorporation in lipid bilayers. Analyst, 138, (24), 7294-7298. (doi:10.1039/C3AN01540H).
 
Jarvis, James, Haies, Ibraheem, Williamson, Phil and Carravetta, Marina (2013) An efficient NMR method for the characterisation of 14N sites through indirect 13C detection. Physical Chemistry Chemical Physics (doi:10.1039/C3CP50787D). (PMID:23589073).
 
Marius, Phedra, de Planque, Maurits R.R. and Williamson, Philip T.F. (2012) Probing the interaction of lipids with the non-annular binding sites of the potassium channel KcsA by magic-angle spinning NMR. Biochimica et Biophysica Acta (BBA) – Biomembranes, 1818, (1), 90-96. (doi:10.1016/j.bbamem.2011.09.017). (PMID:21963409).
 
Marius, Phedra, Leung, Yuk Ming, Piggot, T, Khalid, Syma and Williamson, P.T.F. (2011) Probing the oligomeric state and interaction surfaces of Fukutin-I in dilauroylphosphatidylcholine bilayers. European Biophysical Journal (doi:10.1007/s00249-011-0773-5).
 
Taylor, Garrick F., Wood, Stephen P., Moers, Karsten, Glaubitz, Clemens, Werner, Jorn M. and Williamson, Phillip T.F. (2011) Morphological differences between beta2-microglobulin in fibrils and inclusion bodies. ChemBioChem, 12, (4), 556-558. (doi:10.1002/cbic.201000582).
 
Holdbrook, Daniel A., Leung, Yuk Ming, Piggot, T, Marius, Phedra, Williamson, Phillip T.F. and Khalid, Syma (2010) Stability and membrane orientation of the fukutin transmembrane domain: a combined multiscale molecular dynamics and circular dichroism study. Biochemistry, 49, (51), 10796-10802. (doi:10.1021/bi101743w). (PMID:21105749).
 
Marius, P., Wright, J. N., Findlow, I.S. and Williamson, P.T.F. (2010) Expression and purification of the transmembrane domain of Fukutin-I for biophysical studies. Protein Expression and Purification, 72, (1), 107-112. (doi:10.1016/j.pep.2010.01.019). (PMID:20117215).
 
Marius, P., Wright, J.N., Findlow, Stuart C. and Williamson, P.T.F. (2010) Expression and purification of the transmembrane domain of fukutin-I for biophysical studies. Protein Expression and Purification, 72, (1), 107-112. (doi:10.1016/j.pep.2010.01.019). (In Press).
 
Williamson, P.T.F. (2009) Solid-State NMR for the analysis of high affinity ligand/receptor interactions. Concepts in Magnetic Resonance Part A, 34A, (3), 144-172. (doi:10.1002/cmr.a.20140).
 
Marenchino, Marco, Williamson, Phillip T.F., Murri, Samuel, Zandomeneghi, Giorgia, Wunderli-Allenspach, Heidi, Meier, Beat H. and Kramer, Stefanie D. (2008) Dynamics and cleavability of the alpha-cleavage site of APP(684-726) in different lipid environments. Biophysical Journal, 95, (3), 1460-1473. (doi:10.1529/biophysj.108.129726). (PMID:18390599).
 
Williamson, P.T.F., Verhoeven, A., Miller, K.W., Meier, B.H. and Watts, A. (2007) The conformation of acetylcholine at its target site in the membrane-embedded nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences, 104, (46), 18031-18036. (doi:10.1073/pnas.0704785104).
 
Chandrasekhar, I., Gunsteren, W.F., Zandomeneghi, G., Williamson, P.T.F. and Meier, B.H. (2006) Orientation and conformational preference of leucine-enkephalin at the surface of a hydrated dimyristoylphosphatidylcholine bilayer: NMR and MD simulation. Journal of the American Chemical Society, 128, (1), 159-170. (doi:10.1021/ja054785q).
 
Lindström, Fredrick, Williamson, Philip T.F. and Gröbner, Gerhard (2005) Molecular insight into the electrostatic membrane surface potential by N-14/P-31 MAS NMR spectroscopy: nociceptin-lipid association. Journal of American Chemical Society, 127, (18), 6610-6616. (doi:10.1021/ja042325b).
 
Lindstrom, F., Williamson, P.T.F., Bokvist, M. and Grobner, G. (2005) N-14 and P-31 high resolution MAS NMR provides a way to monitor biological model membrane surfaces and occurring changes upon peptide-association.Biophysical Journal, 88, (1), 142A-142A.
 
Williamson, P.T.F., Zandomeneghi, G., Barrantes, F.J., Watts, A. and Meier, B.H. (2005) Structural and dynamic studies of the gamma-M4 trans-membrane domain of the nicotinic acetylcholine receptor. Molecular Membrane Biology, 22, (6), 485-496. (doi:10.1080/09687860500370653).
 
Lindström, Fredrick, Williamson, Philip T.F. and Gröbner, Gerhard (2005) Molecular insight into the electrostatic membrane surface potential by 14n/31p MAS NMR spectroscopy: nociceptin-lipid association. Journal American Chemical Society, 127, (18), 6610-6616. (doi:10.1021/ja042325b).
 
Verhoeven, A., Williamson, P.T.F., Zimmermann, H., Ernst, M. and Meier, B.H. (2004) Rotational-resonance distance measurements in multi-spin systems. Journal of Magnetic Resonance, 168, (2), 314-326. (doi:10.1016/j.jmr.2004.03.009).
 
Williamson, P.T.F., Meier, B.H. and Watts, A. (2004) Structural and functional studies of the nicotinic acetylcholine receptor by solid-state NMR. European Biophysics Journal, 33, (3), 247-254. (doi:10.1007/s00249-003-0380-1).
 
Hronska, M., van Beek, J.D., Williamson, P.T.F., Vollrath, Fritz and Meier, Beat H. (2004) NMR characterization of native liquid spider dragline silk from Nephila edulis. Biomacromolecules, 5, (3), 834-839. (doi:10.1021/bm0343904).
 
Lindstrom, Fredrik, Sani, Marco., Williamson, Philip.T.F., Bokvist, Marcus and Grobner, Gerhad (2004) Solid state N-14 and P-31 MAS NMR: new tools to study electrostatic binding of peptides on biomembrane surfaces.Biophysical Journal, 86, (1), 19A-19A.
 
Zandomeneghi, G., Tomaselli, M., Williamson, P.T.F. and Meier, B.H. (2003) NMR of bicelles: orientation and mosaic spread of the liquid-crystal director under sample rotation. Journal of Biomolecular Nuclear Magnetic Resonance (NMR), 25, (2), 113-123. (doi:10.1023/A:1022236217018).
 
Zandomeneghi, G., Williamson, P.T.F., Hunkeler, A. and Meier, B.H. (2003) Switched-angle spinning applied to bicelles containing phospholipid-associated peptides. Journal of Biomolecular Nuclear Magnetic Resonance, 25, (2), 125-132. (doi:10.1023/A:1022244025351).
 
Lindstrom, F., Bokvist, M., Williamson, P.T.F. and Grobner, G. (2003) Unspecific membrane association of the GPCR ligand nociceptin studied by 14N, 31P solid-state NMR and ITC calorimetry.Biophysical journal, 84, (2), 278A-278A.
 
Williamson, Philip T.F., Verhoeven, Aswin, Miller, Keith W., Watts, Anthony and Meier, Beat H. (2003) Structural studies of acetylcholine bound to the nicotinic acetylcholine receptor.Biophysical Journal, 84, (2), p.278A.
 
Williamson, P.T.F., Verhoeven, A., Ernst, M. and Meier, B.H. (2003) Determination of internuclear distances in uniformly labeled molecules by rotational-resonance solid-state NMR. Journal of the American Chemical Society, 125, (9), 2718-2722. (doi:10.1021/ja028210u).
 
Williamson, Philip T.F., Verhoeven, Aswin, Ernst, Matthias and Meier, Beat H. (2003) Determination of internuclear distances in uniformly labeled molecules by rotational-resonance solid-state NMR. Journal of the American Chemical Society, 125, (9), 2718-2722. (doi:10.1021/ja028210u).
 
Williamson, P.T.F., Bains, S., Chung, C., Cooke, R. and Watts, A. (2002) Probing the environment of neurotensin whilst bound to the neurotensin receptor by solid state NMR. FEBS Letters, 518, (1-3), 111-115. (doi:10.1016/S0014-5793(02)02656-X).
 
Williamson, P.T.F., Verhoeven, A., Miller, K., Watts, A. and Meier, B. (2002) Structure determination of uniformly labelled ligands in receptor systems: Acetylcholine – A case study.Biophysical Journal, 82, (1), 518A-519A.
 
Bokvist, M., Lindstrom, F., Williamson, P.T.F., Glaubitz, C. and Grobner, G. (2002) Structure and aggregation of membrane-associated A beta peptide explored by solid state NMR and CD.Biophysical Journal, 82, 17A-17A.
 
Williamson, P.T.F., Watts, J.A., Addona, G.H., Miller, K.W. and Watts, A. (2001) Dynamics and orientation of N+(CD3)(3)-bromoacetylcholine bound to its binding site on the nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 98, (5), 2346-2351. (doi:10.1073/pnas.031361698).
 
Grobner, G., Glaubitz, C., Williamson, P.T.F., Hadingham, T. and Watts, A. (2001) Structural features of membrane-bound amyloid-beta peptide determined by solid state NMR.Biophysical Journal, 80, (1), 368A-368A.
 
Williamson, P.T.F, Watts, J.A, Addona, G.H., Miller, K.W. and Watts, A. (2001) Dynamics and orientation of N+(CD3)3-bromoacetylcholine bound to its binding site on the nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America, 98, (5), 2346-2351. (doi:10.1073/pnas.031361698).
 
Williamson, P.T.F., Roth, J.F., Haddingham, T. and Watts, A. (2000) Expression and purification of recombinant neurotensin in Escherichia coli. Protein Expression and Purification, 19, (2), 271-275. (doi:10.1006/prep.2000.1246).
 
Watts, Anthony, Burnett, Ian J., Glaubitz, Clemens, Grobner, Gerhard, Middleton, David A., Spooner, Paul J.R., Watts, Jude A. and Williamson, Phil T.F. (1999) Membrane protein structure determination by solid-state NMR. Natural Product Reports, 16, 419-423. (doi:10.1039/a801189c).

Book Section

Taylor, Garrick F., Marius, Phedra, Ford, Chris and Williamson, Philip T.F. (2013) Solid-state NMR spectroscopy of biopolymers. In, Thomas, Sabu, Durand, Dominique, Chassenieux, Christophe and Jyotishkumar, P. (eds.) Handbook of Biopolymer-Based Materials: From Blends and Composites to Gels and Complex Networks. Chichester, GB, Wiley. (doi:10.1002/9783527652457.ch14).

Conference or Workshop Item

Beaugrand, Maïwenn, Kalsi, Sumit, de Planque, Maurits R.R., Johnson, Christopher D., Wright, J. Neville, Marcotte, Isabelle and Williamson, Phillip T.F. (2013) Expression and purification of a functional hERG pore domain for biophysical and electrophysiological studies. In, 58th Annual Meeting of the Biophysical Society, San Francisco, US, 15 – 19 Feb 2014. (Submitted).

Additional publications

Williamson, P.T.F., Ernst, M. and Meier, B.H. MAS Solid state NMR of isotopically enriched biological samples. In Bio-NMR in drug research, (2003) edited by O. Zerbe (Wiley-VCH)

Williamson, P.T.F., Bains, S.K., Chung, C.,  Cooke, R., Meier B.H. and Watts, A. Characterisation and assignment of uniformly labelled NT(8-13) at the agonist binding site of the G-protein coupled neurotensin receptor. S.R. Kiihne and H.J.M de Groot (eds.), Frontiers in structural biology (2001) Kluwer Publishers, Dordrecht, The Netherlands. 215-226

Watts, I.J. Burnett, C. Glaubitz, G. Gröbner, D.A. Middleton, P.J.R. Spooner, J.A. Watts and Williamson. P.T.F. Membrane protein structure determination by solid state NMR. Natural Product Reports 1999 (16) 419-423

 

Personal


 

 

Comments are closed.