Based in the Institute of Cellular and Molecular Biology, Faculty of Biological Sciences at the University of Leeds. My research group uses cell culture, molecular genetics and microscopy to understand how muscle contracts, how filaments and sarcomeres assemble, how mutations in sarcomeric proteins result in heart and/or skeletal muscle disease and how non-muscle myosins generate force and movement in non-muscle cells.
New: ESF Conference on the 'Emergent Properties of the Cytoskeleton' (Organisers: Michelle Peckham and Claudia Veigel), October 3-8th, 2010 in Spain. For more information, and a list of speakers, see the ESF website.
New Myosin family Tree
The human genome encodes 39 different myosin heavy chain genes (for a Human Myosin family tree, see here). Our main focus is to understand how they work and how they are regulated in cells. For more, see our recent review in 'Soft Matter' . When a predicted coiled coil is really a single -helix, in myosins and other proteins. (Michelle Peckham and Peter J. Knight, Soft Matter, 2009, 5, 2493)
Heart Disease, Actin and Myosin 2 (cardiac and skeletal myosins):About 1 in 500 of us carry a mutation in one of the proteins found in muscle sarcomeres that will lead to an early death from heart failure. About one third of these mutations are in the myosin heavy chain gene found in heart muscle (beta-cardiac myosin). We express mutant beta-cardiac myosins in cultured cells to find out how they affect contraction. Using this approach, we've shown that two mutations result in faster contractions than than normal (Miller, Maycock et al., J. Physiol. 2003), which would have significant effects on power output in the heart. We are now looking at both myosin and actin mutations that cause familial hypertrophic cardiomyopathy, by expressing the mutant proteins in cultured cardiomyocytes, and finding out how they affect contraction. (BHF funded research). |
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This picture shows a cardiomyocyte in culture, which was made by differentiating embryonic stem cells. The stripes show staining for proteins that are organised into a regular repeating pattern in the muscle sarcomeres. The distance between the green stripes is about 2.5 microns.  |
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Hearing Diseases and Myosin 7Hearing loss in some forms of Usher Disease, and non-syndromic deafness, can be caused by mutations in Myosin 7 (see tree). We recently showed (in collaboration with Jim Seller's group at NIH) that myosin 7 has a compact, folded structure when it is inactive, and it extends when it is active. The tip of the tail (the C-terminal FERM - Four point one, Ezrin, Radixin, Moesin domain) is required for this folding as shown in the image to the right. The image shows that the isolated myosin 7a is a monomer. (Yang, Baboolal et al., P.N.A.S. 2009) |
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This shows a single image average for myosin 7a from Drosophila either in the presence (compact form) or in the absence (extended form) of ATP. Below the EM images are two diagrams showing how the different domains are potentially organised in the two molecules. Scale bar 10 nm.
Funded by BBSRC |
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Myosin 10 and single alpha helicesMyosin 10 is similar to myosin 7. We found that it contains a novel structure in its 'neck' called a single alpha helix (SAH) domain (Knight et al., J. Biol. Chem. 2005) that is likely to help this myosin take bigger steps when it interacts with actin. Single alpha helices are often mistaken for coiled coils. See Peckham & Knight 'When a predicted coiled coil is really a single alpha helix', Soft Matter, 2009. (in the press). The SAH domain in the neck of myosin 10 and other myosins (6, and 7) could lengthen the lever as shown below. A lever that consists of three IQ motifs would produce a smaller step size than a lever that contains three IQ motifs and the SAH domain. |
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KinesinWe are also interested in other molecular motors, including kinesin. We recently found that conventional kinesin (kinesin-1, or kif5c) prefers to motor along modified microtubules. It likes tubulin that is missing its C-terminal tyrosine (de-tyrosinated, or 'glu' tubes) the best. (See Dunn et al., 2008, J. Cell. Sci)
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