The cells in our body contain numerous molecular machines that carry out nearly all biological processes essential for life. These machines are built from proteins that are often assembled into complex structures. For example ribosomes contain 80 distinct proteins on a scaffold of four different RNAs. The assembly of such structures from so many parts is a complicated process and inevitably results in ‘leftover’ proteins.
Proteins can be reversibly phosphorylated – phosphate groups are added to proteins by the action of kinase enzymes and can be removed by phosphatases. This controls a huge variety of cellular processes and targeting phosphorylation thus offers a board range of therapeutic opportunities. Indeed, kinases have received much attention in pharmaceutical research, yet phosphatases have been largely untapped.
When cells divide, they must accurately copy their genetic material (DNA) and also ensure that their pattern of gene expression is maintained – genes that were ‘on’ before the cell divides need to remain on in the daughter cell, and genes that were ‘off’ need to remain off. These patterns of gene expression are determined by epigenetic signals, and it is possible to alter these signals to reprogram gene expression.
Neural networks, circuits of neurons, are emerging as the fundamental computational unit of the brain and it is becoming progressively clearer that neural network dysfunction is at the core of a number of psychiatric and neurodegenerative disorders. Yet our ability to target and study specific neural networks remains limited. Until now Rabies virus, which can jump synapses, has been used to investigate neural networks.
Alzheimer’s disease, the most common neurodegenerative disease, is characterised by the formation of filamentous Tau protein inside nerve cells and amyloid-beta peptides outside cells. Despite more than three decades of research into Tau filaments from a range of different neurodegenerative diseases, atomic structures were still lacking.
Dyneins are a family of motor proteins that move along microtubules to transport various important cargos, including proteins and RNAs, to different parts of the cell and are crucial to correct cell function. Gradually, the structure of various components of dynein have been revealed.
The DNA in cells is constantly damaged by both internal activities of the cell and by external factors such as ionising radiation. In order to function correctly, this damage must be repaired, or if it cannot be repaired, the cell must be killed to prevent development of diseases such as cancer. The large protein kinase, ataxia-telangiectasia mutated (ATM), is a vital component of the cell’s DNA repair machinery.
G protein-coupled receptors (GPCRs) form the largest family of membrane-protein receptors and drug targets. With over 800 different family members in humans, GPCRs regulate diverse intracellular signalling cascades in different cell types, tissues and organ systems. Whilst GPCRs sense a plethora of environmental stimuli, the appropriate cellular response is primarily triggered by binding to four major Gα protein families encoded by 16 human genes.
The Wnt signalling pathway is an ancient cell communication pathway that has important roles in development and cancer. Wnt signals elicit context-dependent transcriptional responses by stabilising a cytoplasmic effector called beta-catenin. This controls the embryonic development of tissues and organs in all animals, from the most primitive ones all the way to humans.
DNA in the nucleus is arranged into nucleosomes to produce an 11nm fibre which then intricately folds into high order assemblies. This nuclear organisation – the 3D arrangement of the genome within the nucleus – is critically linked to nuclear processes. Previously it has only been possible to analyse genome organisation across populations of cells.