Fred W. Keeley
Professor
BSc, University of Manitoba, 1961-1965
PhD, University of Manitoba, 1965-1970
Postdoc, Agricultural Research Council UK, 1970-1972
Postdoc, The Hospital for Sick Children, 1972-1973
| Address | Research Institute, The Hospital for Sick Children PGCRL 686 Bay Street Toronto, ON M5G 0A4 |
| Lab Phone | 416-813-6737 |
| Office Phone | 416-813-6704 |
| fwk@sickkids.ca |
Fred Keeley was born and raised in Winnipeg where he completed an undergraduate degree in Chemistry and a PhD in Pharmacology at the University of Manitoba. He spent two years as a Post-Doctoral fellow at the British Agricultural Research Council research establishment near Bristol, England, followed by a Post- Doctoral fellowship in the Department of Biochemistry at the Hospital for Sick Children. He joined the staff of the Research Institute of the Hospital for Sick Children in 1973, and is currently a Senior Scientist in the Molecular Structure and Function Program. From 1995 to 2013 he served as Associate Chief of Research at the Hospital for Sick Children, and held the Heart and Stroke Foundation of Ontario/Robert M. Freedom Chair in Cardiovascular Science at the Hospital for Sick Children from 2003 to 2008 and from 2008 to 2013. Dr. Keeley was first cross-appointed to the University of Toronto in 1975, and is currently Professor in the Department of Biochemistry and the Department of Laboratory Medicine and Pathobiology.
Research Lab
Our laboratory is located on the 21st floor of the newly completed Peter Gilgan Centre for Research and Learning at the Hospital for Sick Children. Our general interest in sequence/structure/function relationships in elastomeric proteins such as elastin includes studies of the evolutionary history of elastins, regulation of expression of the protein in development and disease, the mechanisms for self-assembly of monomeric elastin into its polymeric form, and the effects of sequence variation, including polymorphisms and splice variants, on the elastomeric properties of the elastin polymer. Our structural studies have led to close collaborations involving computational chemistry, solid state and solution NMR, and bioinformatics.
Research Description
Sequence/Structure/Function Relationships Determining the Elastomeric Properties of Elastin
Our laboratory is studying elastin, the major structural protein of the large blood vessels that imparts to these tissues the physical properties of extensibility and elastic recoil that are essential for their physiological function. Our laboratory has had a long-standing interest in the biochemistry of elastin, including its structure/function relationships, its synthesis and assembly in the extracellular matrix, its role in cardiovascular development and diseases such as aneurysms, atherosclerosis and hypertension, and its functional and evolutionary relationship to other glycine-rich, elastin-like structural proteins in a variety of tissues and species. We have identified the crucial role of proline and glycine residues in maintaining conformations consistent with elastomeric behavior and preventing collapse into amyloid structures. As well, we have extended the phylogenetic range of known elastin sequences to include teleost, amphibian and other elastins, providing important new insights into the evolutionary history of elastin and suggesting fundamental design features of the protein that are important for its properties of extension and recoil.
Our laboratory has shown that recombinant polypeptides modeled on the the elastin monomer are capable of self-assembly into fibrillar structures that can be crosslinked and fabricated into macroscopic materials with elastomeric properties mimicking those of native elastin. This information has been used to deconstruct monomeric elastin in order to determine the contributions of sequence, structure and domain arrangements on elastomeric properties. Recombinant elastomeric materials produced in this way have also been investigated for their possible use as tuneable biomimetic materials for tissue replacement and regeneration. Most recently, we are investigating effects of identified sequence polymorphisms in human monomeric elastin on polymeric elastin assembly and material properties, and the possible associations of these polymorphisms with reduced durability and increased susceptibility to later-onset pathology affecting vascular and other elastin-rich tissues.
Awards & Distinctions
2003–2008 — Heart and Stroke Foundation of Ontario/Robert M. Freedom Chair in Cardiovascular Science at the Hospital for Sick Children
2008–2013 — Heart and Stroke Foundation of Ontario/Robert M. Freedom Chair in Cardiovascular Science at the Hospital for Sick Children
1995 - 2013 — Associate Chief, Research Institute, Hospital for Sick Children
Courses Taught
Extra-Departmental Courses
121Y1 Biological Basis of Oral Health and Disease
STF111Y Structure and Function
JCV3063 Advanced Topics in Cardiovascular Sciences- Vascular
LMP406H Pathobiology of the Cardiovascular System
Publications
View all publications on PubMed
Characterization of Lamprin, an Unusual Matrix Protein from Lamprey Cartilage. Implications for Evolution, Structure and Assembly of Elastin and Other Fibrillar Proteins
P. Robson, G. M. Wright, E. Sitarz, A. Maiti, M. Rawat, J. H. Youson and F. W. Keeley
J Biol Chem 268, 1440-1447 (1993) Read
Identification of a GA-Rich Sequence as a Protein-Binding Site in the 3’UTR of Chicken Elastin mRNA with a Potential Role in the Developmental Regulation of Elastin mRNA Stability
Y. Hew, Z. Grzelczak, C. Lau and F. W. Keeley
J Biol Chem 275, 24857-64 (2000) Read
Sequences and Domain Structures of Mammalian, Avian, Amphibian and Teleost Tropoelastins. Clues to the Evolutionary History of Elastins
M. I. Chung, M. Miao, R. J. Stahl, E. Chan, J. Parkinson and F. W. Keeley
Matrix Biology 25, 492-504 (2006) Read
Proline and Glycine Control Protein Self-Organization into Elastomeric or Amyloid Fibrils
S. Rauscher, S. Baud, M. Miao, F. W. Keeley, and R. Pomès
Structure 14, 1667-1676 (2006) Read
Fibrillins, Fibulins and MAGP Modulate the Kinetics and Morphology of In Vitro Self-Assembly of a Recombinant Elastin-like Polypeptide
J. T. Cirulis, C. M. Bellingham, E. C. Davis, D. Hubmacher, D. Reinhardt, R. P. Mecham and F. W. Keeley
Biochemistry 47, 12601-12613 (2008) Read
Proline Periodicity Modulates the Self-Assembly Properties of Elastin-Like Polypeptides
L. D. Muiznieks and F. W. Keeley
J Biol Chem 285, 39779-39789 (2010) Read
Polymorphisms in the Human Tropoelastin gene Modify In Vitro Self-Assembly and Mechanical Properties of Elastin-like Polypeptides
D. He, M. Miao, E. Sitarz, L. Muiznieks, S. Reichheld, R. Stahl, F. W. Keeley and J. Parkinson
PLoS ONE 7(9): e46130. doi:10.1371/journal.pone.0046130 (2012) Read
Sequence and Domain Arrangements Influence Mechanical Properties of Elastin-Like Polymeric Elastomers
M. Miao, E. Sitarz, C. M. Bellingham, E. Won and L. M. Muiznieks and F. W. Keeley
Biopolymers 99, 392-407 (2012) Read
EBP and FKBP65 Modulate In Vitro Self-Assembly of Tropoelastin"
M. Miao, S. Reichheld, L. Muiznieks, Y. Huang and F. W. Keeley
Biochemistry 52, 7731-7741 (2013) Read
Conformational transitions in the crosslinking domains of elastin
S. E. Reichheld, L. D. Muiznieks, R. Stahl, K. Simonetti, S. Sharpe and F. W. Keeley
J Biol Chem 289, 10057-10068 (2014) Read