Contact: Astbury 8.112, +44(0) 113 34 34350,
You can read more about Prof Trinick's interests here:
Muscle structure, molecular motors, bioelasticity, giant proteins, cryo-electron microscopy
Movement is a defining feature of life and in humans skeletal and heart muscles form nearly half the weight of the body. It has been known for >50 years that muscle contracts as a result of relative sliding of thick and thin filaments composed mainly of myosin and actin. This results in shortening of the basic contractile unit, the sarcomere. Although much is known about myosin, actin and other sarcomere proteins in isolated, pure form, none of the major sarcomere structural elements (thick or thin filament, M- or Z-line) has been fully defined in molecular detail, which is a major impediment to understanding muscle action, also growth and wasting.
In addition to their fundamental importance in biology, many diseases originate in sarcomeres, particularly inherited diseases of the heart, whose mechanisms are poorly understood. Sarcomeres are assembled with extraordinary precision yet their proteins last only a few weeks and must constantly be replaced. Precise assembly and regeneration while maintaining activity is especially striking in the heart, which beats ~100,000x/day. We are therefore working to understand sarcomere structure and mechanisms in greater detail.
One of our interests is titin, which is the third most abundant protein of muscle and gives sarcomeres their passive elasticity. Titin is formed from the largest polypetide yet found in nature, with isoforms up to ~3.8 MDa and >30,000 amino acids. Titin molecules are >1 micron long and span between the M- and Z-lines. In the A-band we have proposed that titin regulates precise assembly of thick filaments, which contain exactly 294 myosin molecules. It has recently become clear that mutations in titin are the commonest cause of the heart disease dilated cardiomyopathy (DCM), which affects about 1 in 250 people and is a major cause of death. These mutations are mainly found in the A-band part of titin which binds myosin. I-band titin elastically connects thick filaments to the Z-line; these connections centre thick filaments between Z-discs and ensure that balanced forces are developed by myosin in opposing thick filament halves.
Myosin and actin also form motile systems in many other cells than muscle, although the movements produced can only be seen under a microscope. These other systems are mainly active transport mechanisms that have evolved because passive transport by diffusion would be too slow. Nearly 50 highly divergent non-muscle myosin classes have now been identified from gene sequencing and most cells in the body make several at any one time; most however are otherwise still uncharacterised. We have studied myosins I, II, V, VI and XVIII. Myosin V, for instance, is 0.3% of brain protein and transports a variety of chemical cargoes in vesicles throughout the body. Myosin VI is involved in hearing, balance and cancer metastasis; remarkably, it walks backwards along actin filaments from all other classes so far studied.
We use a wide variety of biophysical techniques but specialise in electron microscopy, which allows us to observe directly protein shapes and how these change to make motile mechanisms. We use stained and dried specimens at room temperature and cryo-electron microscopy of frozen-hydrated specimens at ~-180°C. Most proteins do not function independently but as parts of larger complexes. Electron microscopy is a powerful method for studying such complexes, which usually cannot be crystallised for X-ray diffraction. Recently, cryo-EM has improved substantially and many large complexes are now being solved to atomic or near-atomic resolution. Ultra-fast freezing (~10,000,000°C/sec) used in cryo-EM also facilitates time-resolved studies of mechanism, which is a method we have helped develop.
Member of Graduate School Committee (Panel for Potential Chairs for Appeals Group)