A minor alteration with profound consequences

Long-lived proteins may accumulate a range of modifications over time, including subtle alterations such as side-chain isomerization.

In collaboration wryanith the
Julian group in UC Riverside and Benesch group in Oxford we study the effect of isomerisation of an aspartate residue in αB-crystallin, the most abundant chaperone proteins in the eye lens and within the longest-lived proteins in the body. Malfunction of these proteins is linked to a range of diseases, including cataract.

Our results illustrate how age-related isomerization of amino acid residues, which may seem to be only a minor structural perturbation, can disrupt native structural interactions with profound consequences for protein assembly and activity.

Lyon, Y.A., Collier, M.P., Riggs, D.L., Degiacomi, M.T., Benesch, J.L.P., Julian, R.R. (2019). Structural and functional consequences of age-related isomerization in α-crystallins, Journal of Biological Chemisty

Celebration of Native Mass Spectrometry

Matteo attended the conference “celebration of native mass spectrometry” in Oxford, where he presented his protein integrative modelling methods leveraging on mass spectrometry data. An exciting venue, and a great opportunity meet old friends from the mass spec community!

Matteo then joined Venkat for a trip to London, where they visited Prof. Vittorio Bellotti at the Royal Free Hospital. Matteo delivered a presentation on means for computational modelling to inform biomedical research.

No presentation on integrative modelling is complete without either a LEGO or an IKEA furniture analogy.

Cover Article in JBC

JBC_coverOur image was selected as a cover article for the 21st December edition of JBC!

The image represents different orientations of the tetrahedral assembly of a wheat small heat shock protein (sHSP). These proteins form dimers, that in turn assemble in more complex architectures.

In our work we show that sHSP dimers (a single one highlighted in yellow in the image) are in equilibrium with the oligomeric form and act as the initial encounter species to capture denaturing substrates.

[image produced with VMD with Tachyon ray tracing, and composed with Gimp]

It takes a dimer to tango


Under changes in conditions as diverse as temperature, oxidation or pH, proteins in an organism may undergo harmful denaturation. Small Heat Shock proteins act as “paramedics of the cell”: during such events they quicky intervene by binding nascently unfolding proteins, leading them to refolding or denaturation pathways. Small heat shock proteins are ubiquitous in all kingdoms of life, but especially effective in plants: after all, plants cannot escape from harsh environmental conditions!

Collaborating with Benesch (University of Oxford) and Vierling (UMass) groups, we have contributed to shedding light into the mode of action of small Heat Shock Proteins in wheat and pea.

We describe a mechanism whereby dimers of these proteins are responsible for capturing their substrate, before assemblying into larger complexes. With our own integrative modelling methods using distance restraints and collision cross-section measurements, we  demonstrate that small heat shock protein dimers assemble into characteristic tetrahedral structures (see on the right).

These results point towards ways to design small heat shock proteins customized to function at desired temperatures.

Santhanagopalan I., Degiacomi M.T., Shepherd D.A., Hochberg G.K.A., Justin L.P. Benesch J.L.P.,  Vierling E., (2018). It takes a dimer to tango: Oligomeric small heat shock proteins dissociate to capture substrate, Journal of Biological Chemisty

Mutation, where are you?

Our homology model of TBC1D24 is featured in a journal article on Human Molecular Genetics. Mutations in this protein are responsible for a broad range of diseases, including epilepsy, DOORS syndrome and hearing loss.


Our model complements the titanic experimental effort of Dr. Mattéa Finelli and collaborators, unveiling that TBC1D24 is crucial for normal presynaptic function, and that disease-causing mutations affect neuronal development and survival.

M. Finelli et al, The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neuron, Human Molecular Genetics, 2018

Venkat joins the group!

Welcome to Dr. Venkata Krishnan Ramaswamy, the first PDRA of our group! Venkat has a background in pharmacoinformatics, and molecular modelling, acquired during his graduate studies in NIPER (S.A.S. Nagar, India) and PhD University of Cagliary (Italy). In our group, Venkat will develop and apply methods combining molecular dynamics simulations and deep learning to characterize protein conformational space.

Welcome to Samuel!

Welcome to Samuel Musson, who joins us this academic year for his Masters project. Samuel, a Durham University student in Chemistry, will focus on the characterization of peptide-lipid interactions.