Publication highlights

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Explore a selection of research case studies from the past five years.

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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Synthetic sugars

Sweet signals: tracking crucial cell messengers for the first time

Researchers at the Crick and Imperial College report a method to characterise and track sugar-coated cell sensors called proteoglycans using click chemistry. Through a 'bump and hole' engineering technique, they modified a hole in an enzyme and a bump in a sugar, to alter an enzyme that glues the two together so it accepts a bumped version of the sugar. This modified sugar contains a chemical tag which means it can be traced using click chemistry, such as attaching a fluorescent molecule to 'see' the molecule by imaging, or a molecule acting like an anchor to isolate and further study it. In the future, these molecules could be tagged and tracked in different contexts, or proteoglycan function could be altered by replacing the sugar chain with a different biological or synthetic molecule.

Xylosyltransferase engineering to manipulate proteoglycans in mammalian cells

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Published in Nature Chemical Biology

Published

Limb malformation in PRKCA mutations

Discovery reveals new understanding of cancer-driving proteins in rare brain tumours and beyond

Scientists at the Crick and Barts Cancer Institute (Queen Mary University of London) have discovered that a single letter change in the PRKCA gene drives a rare and hard-to-treat brain cancer, chordoid glioma. The PRKCA gene contains instructions for making a protein called protein kinase C alpha (PKCa). Until now, many believed blocking kinases would be useful for treating cancer, but in this study the team discovered that the mutation in PRKCA blocks the kinase but paradoxically drives tumour growth. This was because it became locked in a shape that allowed it to promote cancer cell growth signalling and because it interacted with epigenetic regulators in a way that promoted cancer growth.

The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice

Published in Science Signaling

Published

Fanconi Anaemia pathway

How FANCM activates the Fanconi Anaemia DNA repair pathway

Fanconi Anemia is a devastating genetic disease characterised by genome instability, developmental defects, and cancer predisposition, involving defects in the FA DNA repair pathway. Central to the FA pathway is the FANCM protein, which acts as both a DNA damage sensor to modify another protein called FANCD2, and as a fascinating motor protein that “zips up” DNA. This report is the first comprehensive structural and mechanistic understanding of how FANCM recognises DNA damage and activates modification of the FANCD2 and FANCI proteins through a process called monoubiquitination. The paper reveals how FANCM evolved from being a DNA repair motor protein into a complex sensor coupling DNA damage recognition to selective pathway activation.

Structural basis of Fanconi anemia pathway activation by FANCM

Published in EMBO Journal

Published

Kinase profile tests

Identifying signalling networks in MEN2 cancer patients

Researchers at the Crick and the University of York with clinicians from Great Ormond Street and Guy’s and St Thomas’ Hospitals have investigated all the kinase enzymes expressed (the kinome) in children with a disease called Multiple Endocrine Neoplasia Type 2 (MEN2), to identify new therapeutic markers and targets. This autosomal dominant disease leads to several cancers including the development of thyroid cancer and is caused by pathogenic variants in the receptor tyrosine kinase RET. But the development and progression of these tumours are not always predictable, even within families with the same RET pathogenic variant. This study identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, each of which were subsequently validated in patient thyroid tissue.

Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer

Published in npj Precision Oncology

Published

Diagram of the aPKC-Par6 enzyme

Understanding a key mechanism for cell polarity

Researchers in the Signalling and Structural Biology Lab have described a near-complete multisite phosphorylation reaction cycle for the aPKC-Par6 kinase and Lgl substrate. This mechanism explains how a trapped Lgl phospho-intermediate antagonises aPKC-Par6 until it encounters Cdc42-GTP, in an assembly required for cell polarity maintenance.

Capture, mutual inhibition and release mechanism for aPKC-Par6 and its multisite polarity substrate Lgl

Published in Nature Structural & Molecular Biology

Published

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A sticky role for GDNF in synaptic connectivity

A protein called GDNF is under investigation as a neuroprotective agent in Parkinson’s disease. Beyond its well-characterised therapeutic potential, GDNF also plays a further role in promoting synaptic adhesion in hippocampal neurons. Researchers in the McDonald lab at the Crick uncovered the molecular mechanism through which GDNF drives adhesion between two synaptic membranes. This occurs through the formation of a unique assembly of ten subunits with another receptor called GFRa1. They reconstituted this adhesion complex between membranes and imaged this process by X-ray crystallography and cryo-electron tomography. Its role as a synaptic organising complex was validated by counting dendritic spines in rat hippocampal neurons. Finally, they found that the assembly was disrupted by interaction with either the RET receptor or proteoglycans, impacting on neuronal synapse formation. These findings suggest GDNF has a more complex relationship to neuronal function than previously thought, with its signalling outputs dependent on the cellular context.

Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly

Published in Nature Communications

Published

Synthetic sugars

Molecular decision making in glycosaminoglycan synthesis

Cell-surface and secreted proteins play critical roles in human development, growth factor signalling, and cell adhesion. Proteoglycans are an important subset of these proteins and are modified with long chains of sugar molecules called Glycosaminoglycans (GAGs) such as heparan sulphate (HS) or chondroitin sulphate (CS), but they all start with the same four sugars – only after the addition of the fifth sugar is the fate of the growing chain sealed.

While protein and DNA synthesis are template-driven, from DNA or RNA, synthesis of the proteoglycan GAG chains are not. In a collaboration between the Crick and Imperial, the researchers devised a synthesis system to allow precise control of eight of the enzymes in the biosynthesis pathway. They discovered that chrondroitin sulphate is the “default” modification, and that the enzyme responsible for priming chrondroitin sulphate synthesis modifies all sites equally. They also found that the enzyme responsible for priming heparan sulphate synthesis (EXTL3) has a positively charged patch that interacts with negatively charged amino acids near the attachment site and will only modify certain substrates. This will help to predict how mutations surrounding the glycosaminoglycan attachment sites could be implicated in diseases like cancer or developmental conditions.

Molecular mechanism of decision-making in glycosaminoglycan biosynthesis

Published in Nature Communications

Published

Researchers identify new PKCε target as key to successful cell division

Researchers in the Parker lab have unpicked the action of protein kinase C (PKC) in modulating cell growth and division. The team developed a novel trap for proteins regulated by PKC by engineering UV-photocrosslinkable amino acids into PKCε to produce a sort of molecular flypaper. They captured a previously unknown PKCε target, the RNA-binding protein SERBP1, and showed that SERBP1 was required for successful chromosome segregation and cell division. Their work provides a new insight into how cells protect their genome during division and also which regulatory processes could play a key role when cells become cancerous.

A genetically-encoded crosslinker screen identifies SERBP1 as a PKCε substrate influencing translation and cell division

Published in Nature Communications

Published

A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

New research from the McDonald lab combined crystallography and cryo-electron microscopy to reveal how the RET receptor, tyrosine kinase, recognises different GDNF family ligand/co-receptor pairs.

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Published in Structure

Published

Metabolic precision labeling enables selective probing of O-linked N-acetylgalactosamine glycosylation

The first publication from our group at the Crick comprises the development of a precision tool to understand O-GalNAc glycosylation, one of the most abundant and disease-relevant types of glycans. We apply the technique to run state-of-the-art methods of biology, including chemical glycoproteomics with the Proteomics STP and a genome-wise CRISPR screen with collaborators from Stanford. We also collaborate in-house with Vivian Li to apply the probe to imaging intestinal organoids.

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Published in Proceedings of the National Academy of Sciences of the United States of America

Published

RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability

This paper shows that the ArhGAP9/12/15/27 and ArhGAP32/33 families of rhoGAPs are RPEL proteins whose activity is coupled to G-actin concentration. G-actin forms a 1:1 complex with these ArhGAPs, interacting with an RPEL motif located between the PH and GAP domains, thereby inhibiting their GAP activity. Mutations that block G-actin binding exhibit elevated GAP activity towards their substrate GTPases Rac and Cdc42. Strikingly, treatment of cells with drugs enhancing or inhibiting G-actin/ArhGAP interaction has corresponding effects on Rac GTP loading. These results establish a novel homeostatic feedback loop, in which ArhGAP12-family (and presumably ArhGAP32-family) GAP activity increases when G-actin levels become limiting.

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Published in Nature Cell Biology

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.