Insight on Research


Folate and formaldehyde: from vitamin to genotoxin to DNA building block

Cell growth requires the synthesis of molecules, such as nucleotides to make DNA and amino acids to make proteins. One essential building block of these is the one carbon unit. This is produced by the one carbon (1C) cycle, which requires the vitamin folate and the amino acid serine (the main source of the 1C unit). 1C metabolism is important for human health, and folate deficiency causes birth defects, nerve damage and anaemia.

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Amino acid homorepeats influence the function and evolution of proteins

A section of a protein containing an amino acid homorepeat.

Amino acids are the building blocks of proteins. Just twenty different amino acids are strung together in different orders – like beads – to build all the proteins in living organisms. When a single type of amino acid is found consecutively within a protein, this is known as a homorepeat. Abnormal variation in the length of amino acid homorepeats has long been known to be associated with disease, such as Huntington’s.

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Mechanism for cleaning up leftover proteins

Clearing up leftover parts of a complex machine

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.

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Uncovering the action of a selective holophosphatase inhibitor

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.

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Reprogramming gene expression with small molecules

A small molecule stabilises a secondary structure in replicating DNA

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.

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A new tool to study neural networks

Diagram to show how use of SiR allows permanent labelling, manipulation and genetic alterations of neural networks

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.

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First atomic structures of Tau filaments from Alzheimer’s disease brain

Tau filament structures

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.

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First 3D structure of the complete human dynein

Process of dynein’s activation

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.

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Dynamic structure of human DNA repair enzyme, ATM, revealed

Dynamic structures ATM graphic

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.

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The key to GPCR-G protein selectivity

GPCR-G Protein key graphic

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.

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