RICERCA ITALIANA     

Theoretical and experimental approach to non-native states of proteins: formation of amyloid fibrils, unstructured and unfolded proteins.

Università degli Studi di Padova

Abstract

Understanding the process through which proteins fold into their native structures lies at the heart of modern molecular and cellular biology:
How does an unstructured chain of aminoacids, devoid of any biological activity, fold into a well defined three dimensional structure, the native state, where biological activity is performed? Understanding protein folding implies deciphering the second half of the
genetic code, the complex mechanisms that are necessary for the conversion of linear sequences of amino acids into biological activity.
The presence of several protein chains may induce a non correct folding (misfolding) by driving the formation of stable unsoluble aggregates, amyloid fibrils, known to be involved in many terrible diseases. Aggregation mechanisms and the very structure of amyloids are poorly understood and any insight gained could provide a crucial help in devising new medical strategies. Others non native aspects of proteins, such as denaturated states and intrinsically unstructured proteins can hide important information to unveil the problem of folding.
Recently computational power has reached the possibility to start a full scale attack of some realistic situations where "all" degrees of freedom are considered during the time evolution of the system. However the ability to simulate (in silico) in full details the dynamics of proteins and solvent, does not necessarily imply one is able to recognize the key factors determining >>>

Principal Investigator

Amos MARITAN Università degli Studi di PADOVA

Research Objectives

The common research topic of our network is the protein folding problem, i.e. the prediction of the protein 3D-structure from the amino acid sequence.
Many potentials applications of these studies can be envisaged in the fields of fundamental biochemical research, medicine and biotechnology.
In recent years, due to the great achievements of biotechnologies, there has been an amazing increase in the number of protein sequences determined and become available to the scientific community. This information, however, is still not sufficient for an understanding of the role of these molecules inside the cell as it is known that the biochemical function of a protein is closely related to its tridimensional structure.. At present only about 1 per cent of structures corresponding to known sequences have been solved and the number of known sequences continues to increase faster than the number of solved structure. A detailed knowledge of the protein folding process will also provide useful information to treat such diseases as Alzheimer's disease,cystic fibrosis and Creutzfeld-Jacob's disease. In all these cases, the cell is poisoned by the deposit of insoluble structured fibrillar aggregates known as amyloid fibrils, resulting from the aggregation of folding intermediates.
The social impact of these diseases is exemplified by the case of Alzheimer: this disease afflict 10 per cent of people over 65 years old and 50 per cent of people over 85.

In >>>

Timescale

24 months

National and international background

Biological organisms rely on the correct functioning of thousands of different proteins, whose function/malfunction is largely determined by their three-dimensional structure. A protein is a linear chain of a particular sequence of monomer units, the amino acids. This sequence is encoded in the genomes of the organisms. Genome sequencing projects have provided nearly complete lists of macromolecules present in an organism. The next step in this emerging field of research might be the NIH Protein Structure Initiative (http://www.nigms.nih.gov/psi) whose aim is to make the three-dimensional atomic-level structures of most proteins easily obtainable from knowledge of their corresponding DNA sequences. Hopefully, the complete determination of the structure of proteins that are representative of a given protein family may help in determining, by sequence similarity, the structure of protein homologues. This may be seen as a compromise between the need for a complete characterization of protein structures and the difficulty to understand the process by which a polypeptide chain reaches its biologically active three-dimensional structure, or the protein folding problem, which remains, up to date, one of the major problems of molecular biology.

The research units involved in this project (Bari, Firenze, Padova, Roma and Venezia) and the ones strictly collaborating with them (Cambridge (Prof. Dobson), Lausanne (Prof. Stasiak), Munich (Prof. Frey), PennState (Prof >>>