Structural studies of proteins involved in neurodegenerative and muscular diseases 2

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."

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.