Structural studies of proteins involved in neurodegenerative and muscular diseases 2
Lead Research Organisation:
King's College London
Department Name: UNLISTED
Abstract
The accomplishment of the human genome together with the fast progresses made in gene mapping technology have opened for the first time the possibility of approaching hereditary disorders at a molecular level. We approach the study of human diseases by understanding their structure/function relationship. The role of the molecular structure in modern biology and medicine may be directly appreciated if we consider that structure determination of the DNA, the molecule which contains the whole genetic information, unveiled the secret of life. Our laboratory focuses on determining the 3D structure of proteins with specific interest for proteins involved in neurodegenerative diseases such as the Huntington Chorea, Friedreich ataxia, and Fragile X syndrome and muscular pathologies such as different types of cardio-myopathies. Despite the different symptoms, these diseases, all incurable, share the fact that in affected patients, the proteins encoded by the corresponding genes are produced in altered forms, or in smaller quantity down to their complete absence. By determining the shape of the proteins involved we can then understand the role of these mutations on the protein functions and ultimately design new therapeutical strategies. We use a combination of biochemical and biophysical techniques which help us to reconstruct the cellular role of the proteins of interest and characterise their structure/function relationship."
Technical Summary
We focus on neurodegeneration and muscular pathologies.||A molecular approach to human genetic diseases More than 12 human genetic diseases have been associated with expansions of nucleotide repeats in their corresponding genes, all identified in the last 10 years. These diseases, currently incurable, are interesting both for their impact in the human population and for the unusual pattern of genetic behaviour. They are grouped into two sub-families according to whether the expansion occurs in coding or non-coding regions. In our group we have started an integrated approach which makes use of different biochemical and biophysical techniques to study the structure and function of the proteins encoded by several genes of the trinucleotide expansion family. Amongst them are FMRP, the protein responsible for fragile x and frataxin, the protein involved for Friedreichs ataxia. We want to understand the cellular role of these proteins and describe the mechanism of molecular recognition with their binding partners. We have also recently setup a systems biology project which aims at understanding the process of iron-sulfur cluster formation, in which frataxin is involved.||How muscles are assembled and regulated Understanding the molecular bases of muscle contraction has been one of the main research topics in biology for the last decades. Besides actin and myosin, which are the main players in muscle contraction, many other proteins have an essential role in determining muscle assembly and regulation. Several interactions have been described recently which are essential to anchor the muscle filaments to the modular proteins, such as titin, nebulin, and alpha-actinin. Dysfunctions in the interactions cause different types of cardio-myopathies and other muscle diseases. We are currently working to determine the structure of a number of protein complexes. This information will eventually allow us to reconstruct the muscle ultrastructure.
Organisations
People |
ORCID iD |
Annalisa Pastore (Principal Investigator) |
Publications
Faggiano S
(2016)
The missing links to link ubiquitin: Methods for the enzymatic production of polyubiquitin chains.
in Analytical biochemistry
Chiki A
(2017)
Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6.
in Angewandte Chemie (International ed. in English)
Pastore A
(2017)
The Emperor's new clothes: Myths and truths of in-cell NMR.
in Archives of biochemistry and biophysics
Yan R
(2015)
Ferredoxin, in conjunction with NADPH and ferredoxin-NADP reductase, transfers electrons to the IscS/IscU complex to promote iron-sulfur cluster assembly.
in Biochimica et biophysica acta
Adrover M
(2015)
Anatomy of an iron-sulfur cluster scaffold protein: Understanding the determinants of [2Fe-2S] cluster stability on IscU.
in Biochimica et biophysica acta
Temussi PA
(2021)
The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility.
in BioEssays : news and reviews in molecular, cellular and developmental biology
Aprile FA
(2021)
Man does not live by intrinsically unstructured proteins alone: The role of structured regions in aggregation.
in BioEssays : news and reviews in molecular, cellular and developmental biology
De Chiara C
(2014)
Chemical shift assignment of the ataxin-1 AXH domain in complex with a CIC ligand peptide.
in Biomolecular NMR assignments
Sicorello A
(2018)
The Structural Properties in Solution of the Intrinsically Mixed Folded Protein Ataxin-3.
in Biophysical journal
De Chiara C
(2013)
Self-assembly and conformational heterogeneity of the AXH domain of ataxin-1: an unusual example of a chameleon fold.
in Biophysical journal
Description | Newton Fellowship |
Amount | £96,000 (GBP) |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2015 |
End | 10/2017 |
Description | Understanding the aggregation properties of TDP43 in FTD |
Amount | £5,000,000 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2021 |
Title | Production of mylated peptides |
Description | We developed a robust method to glycate peptides |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | This allows the facile production of peptides with this post-translational modification |
Title | Production of post-translational modification in proteins |
Description | We designed a strategy to ubiquitinate ataxin-3 |
Type Of Material | Biological samples |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | We have provided a new methodology to produce suitable amounts of mono-ubiquitinated ataxin-3 |
Title | a new model for the causes of Friedreich's ataxia |
Description | We identified the function of frataxin and provided a model for how its absence causes the disease |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | We provided information on how to mutate proteins for validating our model. |
Title | nanoFTIR |
Description | We have used in cell nanoFTIR to study the metabolic landscape of disease |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | It allows to follow the metabolic status of cells from patients |
Description | Rational design of RNA aptamers |
Organisation | Italian Institute of Technology (Istituto Italiano di Tecnologia IIT) |
Department | Neuroscience and Brain Technologies IIT |
Country | Italy |
Sector | Academic/University |
PI Contribution | We are developing RNA aptamers against TDP-43 |
Collaborator Contribution | The partner Gian Gaetnao Tartaglia is the author of the software used for the prediction. |
Impact | We have held together a grant from MNDA and published four papers together. We are now in the process of sending off a manuscript and a grant application to ADDF. |
Start Year | 2016 |
Description | Studies of misfolding diseases: polyQ and prion diseases |
Organisation | French National Institute of Agricultural Research |
Country | France |
Sector | Academic/University |
PI Contribution | NMR spectrometr time, know-how on NMR structural determination |
Collaborator Contribution | know-how on light scatterins, calorimetry and kinetics. |
Impact | Two publications in prreparation |
Start Year | 2008 |
Description | Studies of the frataxin function |
Organisation | Free University of Brussels |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We have developed an assay which has allowed us to elucidate the function of frataxin |
Collaborator Contribution | co-authored publications and in vivo experiments to test our functional hypotheses |
Impact | As a result of this collaboration we are now part of an EU grant awarded for 2009-2012. Pandolfo, M., Pastore, A. (2008) The pathogenesis of Friedreich ataxia and the structure and function of frataxinJ. of Neurol. 256 Suppl 1:9-17 |
Start Year | 2010 |
Description | The mechanism of protein aggregation |
Organisation | Moscow State University |
Department | Biochemistry Department |
Country | Russian Federation |
Sector | Academic/University |
PI Contribution | We have been collaborating on the effects of metals on the aggregation of the Abeta peptides. |
Collaborator Contribution | They produced the peptide and analysed the data collected in London |
Impact | We have been accepted a paper in Scientific reports. |
Description | Press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Press release for our work on Friedreich's ataxia The promotion of reserach on this disease. The establishment of a EU network to support the research further. |
Year(s) Of Engagement Activity | 2009 |
Description | Publication of a science dissemination in Frontiers for young minds |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | I published an article in frontiers for Young Minds which is directed to children in the range of 8 to 16 years old. This initiative is meant to disseminate research among young people. |
Year(s) Of Engagement Activity | 2017 |
Description | Seminar to International Rotary Club |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The meeting was to sensibilise general audience about dementia. |
Year(s) Of Engagement Activity | 2020 |