Davies, Peter L - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

We are studying the relationship between structure and function in two different types of proteins: antifreeze proteins (AFPs), which help organisms resist or tolerate freezing, and calpains, enzymes that selectively cut proteins within the cell in response to calcium signals. Antifreeze proteins are found in some fishes, insects, plants and microorganisms. They bind to ice crystals and prevent them from growing to a size where they would damage the host. Our research involves the isolation and characterization of antifreeze proteins from different sources, the study of their evolution, and the cloning and expression of their genes to produce recombinant proteins for 3-D structural analysis by NMR and/or X-ray crystallography. They are proving to have remarkably diverse structures. We are trying to identify their ice-binding sites/residues using site-directed dfmutagenesis in order to learn more about their mechanism(s) of action and what structural features are required for binding to ice. We are also trying to design new AFPs based on this information and to engineer improvements in existing AFPs

研究领域

We are studying the relationship between structure and function in three different types of proteins: antifreeze proteins (AFPs), which help organisms to resist or tolerate freezing; bacterial adhesins, which play a role in biofilm formation and infection; and calpains, enzymes that selectively cut proteins within the cell in response to calcium signals. (Funded by CIHR and NSERC) Antifreeze proteins are found in some fishes, insects, plants and microorganisms. They bind to ice crystals and prevent them from growing to a size where they would damage the host. Our research involves the isolation and characterization of antifreeze proteins from different sources, the study of their evolution, and the cloning and expression of their genes to produce recombinant proteins for 3-D structural analysis by NMR and/or X-ray crystallography. AFPs are proving to have remarkably diverse structures. We are trying to identify their ice-binding sites/residues using site-directed mutagenesis in order to learn more about their mechanism(s) of action and what structural features are required for binding to ice. We are also engineering superior AFPs based on this information, and are applying them to the sub-zero storage of organs, tissues and cells. Bacterial adhesins are long, thin proteins attached to the outer membrane of bacteria, which anchor their hosts to various surfaces where the bacteria can form biofilms. Structural characterization and functional analysis of all the adhesins are revealing methods for blocking biofilm formation that will be useful in preventing infections. Calpains are complex, multi-domain calcium-dependent proteases involved in calcium signaling. We are studying their mechanism of activation and inhibition, and are using peptide and combinatorial compound libraries to develop calpain-specific inhibitors and substrates. The latter will be used to better define the physiological roles of calpain, and as leads for developing drugs to help prevent the calpain-mediated damage associated with heart attacks, stroke, neurodegeneration, and muscular dystrophy.

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Bar-Dolev, M., Bernheim, R., Guo, S., Davies, P.L., Braslavsky, I. (2016) Putting life on ice: Bacteria that bind to frozen water. RSC Interface. 2016 Aug;13(121). pii: 20160210. doi: 10.1098/rsif.2016.0210. PubMed: 27534698 Bar-Dolev, M., Braslavsky, I., Davies, P.L. (2016) Antifreeze protein function. Ann. Rev. Biochem. 85, 515-542. PubMed: 27145844 Basu, K., Campbell, R.L., Guo, S., Sun, T., Davies, P.L. (2016) Modeling repetitive, non-globular proteins. Protein Sci. 25 (5), 946-58 Feb 23. doi: 10.1002/pro.2907. [Epub ahead of print] Review. PubMed:26914323 Basu, K., Wasserman, S.S., Jeronimo, P.S., Graham, L.A., Davies, P.L. (2016) Intermediate activity of midge antifreeze protein is due to a tyrosine-rich ice-binding site and atypical ice plane affinity. FEBS J. 283 (8) 2016 Feb 20. doi: 10.1111/febs.13687. [Epub ahead of print] PubMed:26896764 Sun, T., Davies, P.L., Walker, V.K. (2015) Structural basis for the inhibition of gas hydrates by alpha-helical antifreeze proteins. Biophys. J. 109, 1698-1705. PubMed: 26488661 Stevens, C., Drori, R., Zalis, S., Braslavsky, I., Davies, P.L. (2015) Dendrimer-linked antifreeze proteins have superior activity and thermal recovery. Bioconjugate Chemistry. PubMed: 26267368 Basu, K., Graham, L.A., Campbell, R.L., Davies, P.L. (2015) Flies expand the repertoire of protein structures that bind ice. PNAS 112(3), 737-742. PubMed: 25561557 Sun,T., Feng-Hsu Lin, F-H., Campbell, R.L., Allingham, J.S., and Davies, P.L. (2014) An antifreeze protein folds with an interior network of over 400 semi-clathrate waters. Science, 343(6172), 795-8 PubMed: 24531972 Access the recommendation on F1000Prime Vance, T.D.R., Olijve, L.L.C., Campbell, R.L., Voets, I.K., Davies, P.L., Guo, S. (2014) Ca2+-stabilized adhesin helps an Antarctic bacterium reach out and bind ice. Bioscience Reports 34(4). PubMed: 24892750 Davies, P.L. (2014) Ice-binding proteins: a remarkable diversity of structures for stopping and starting ice growth. Trends in Biochemical Sciences 39(11), 548-555. PubMed: 25440715 Graham L.A, Hobbs R.S, Fletcher G.L, Davies P.L. (2013) Helical antifreeze proteins have independently evolved in fishes on four occasions. PLoS ONE 8(12), e81285 PubMed: 24324684 Guo, S., Garnham, C.P., Partha, S.K., Campbell, R.L., Allingham, J.S., Davies, P.L. (2013) Role of Ca2+ in folding the tandem β-sandwich extender domains of a bacterial ice-binding adhesion. FEBS Journal Ref. no.: FJ-13-0467.R1.PubMed: 24024640 Celik Y., Drori R., Pertaya-Braun N., Altan A., Barton T., Bar-Dolev M., Groisman A., Davies P.L., Braslavsky I. (2013) Microfluidic experiments reveal that antifreeze proteins bound to ice crystals suffice to prevent their growth. Proc Natl Acad Sci U S A. 110,1309-14 PubMed: 23300286 Guo, S., Garnham, C.P., Whitney J.C., Graham, L.A. and Davies, P.L. (2012) Re-evaluation of a bacterial antifreeze protein as an adhesin with ice-binding activity. PLoS ONE 7, e48805 PubMed: 23144980 Garnham C.P., Nishimiya Y., Tsuda S., Davies P.L. (2012) Engineering a naturally inactive isoform of type III antifreeze protein into one that can stop the growth of ice. FEBS Lett. 586(21), 3876-81. PubMed: 23017208 Campbell R.L., Davies P.L. (2012) Structure-function relationships in calpains. Biochem J. 447, 335-51 PubMed: 23035980 Middleton, A.J., Marshall, C.B., Faucher, F., Bar-Dolev, M., Braslavsky, I., Campbell, R.L., Walker, V.K. and Davies, P.L. (2012) Antifreeze protein from freeze-tolerant grass has a beta-roll fold with an irregularly structured ice-binding site. J. Mol. Biol. 416, 713-724 PubMed: 22306740 Garnham, C.P., Campbell, R.L., Walker, V.K and Davies, P.L. (2011) Novel dimeric β-helical model of an ice nucleation protein with bridged active sites. BMC Structural Biology 11, 36 PubMed: 21951648 Free PDF at BioMed Central Lin, F.H.,Davies, P.L. and Graham, L.A. (2011) The Thr- and Ala-rich hyperactive antifreeze protein from inch worm folds as a flat silk-like β-helix. Biochemistry 50, 4467-4478. PubMed: 21486083 Garnham, C.P., Campbell, R.L. and Davies, P.L. (2011) Anchored clathrate waters bind antifreeze proteins to ice. PNAS 108, 7363-7367. PubMed: 21482800 PubMed Central: PMC3088597 Garnham, C.P,. Natarajan, A,. Middleton, A.J., Kuiper, M.J., Braslavsky, I., Davies, P.L. (2010) Compound ice-binding site of an antifreeze protein revealed by mutagenesis and fluorescent tagging. Biochemistry 49, 9063-9071. PubMed: 20853841 Mok, Y.F., Lin, F.H., Graham, L.A., Celik, Y. Braslavsky, I., Davies, P.L. (2010) Structural basis for the superior activity of the large isoform of snow flea antifreeze protein. Biochemistry 49, 2593-2603. PubMed: 20158269 Celik Y., Graham, L.A., Mok, Y.F., Bar, M., Davies, P.L., Braslavsky I. (2010) Superheating of ice crystals in antifreeze protein solutions. Proc Natl Acad Sci U S A. 107, 5423-5428. PubMed: 20215465 Garnham, C.P., Hanna, R.A., Chou, J.S., Low, K.E., Gourlay, K., Campbell, R.L., Beckmann, J.S. and Davies, P.L. (2009) Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3. Biochemistry 48, 3457-3467. PubMed: 19226146 Middleton, A.J., Brown, A.M., Davies, P.L. and Walker, V.K. (2009) Identification of the ice-binding face of a plant antifreeze protein. FEBS Lett. 583, 815-819. PubMed: 19185572