N-Terminal Acetylation of Proteins

The first 50 amino acids on a protein and the co-translational modifications associated with these residues define some important properties of the proteins (stability, interaction, location). Their deregulation is associated with the development of several pathologies.

More than 85% of eukaryotic proteins are acetylated on the amino terminal. However, there are few examples in which the biological relevance of this modification has been described. We have confirmed that N-terminal acetyltransferase NatB activity is essential for the organization and proper function of the actin cytoskeleton such that inhibition of the enzyme blocks cell motility, thereby affecting tropomyosin function. In addition, the catalytic subunit of the NatB enzyme, Naa20, is overexpressed in human and murine hepatocarcinoma. Therefore, we have identified small molecules that are capable of inhibiting the NatB enzyme that may be the basis of a new antitumor and antimetastatic therapy.

We have created genetically modified rats that lack the accessory subunit of the NatB enzyme, Naa25. Therefore, they also lack the Naa20 subunit for defining the antitumor potential of the inhibition from the NatB enzyme characterization of toxic effects observed when the NabB enzyme is continuously inhibited.

In collaboration with the CIMA Neurosciences Program, we are measuring the relevance of N-terminal acetylation of the alpha-synuclein, a modification catalyzed by the NatB enzyme, in diseases associated to this protein (Parkinson's and other neurodegenerative diseases). Specifically, we are studying how this modification affects protein aggregation and stability and the pathogenesis of the most deleterious forms of alpha-synuclein. The objective is to identify new treatment strategies aimed at decreasing the pathological aggregation of this protein.

In addition, in collaboration with the University of Bergen (Norway) and the Cold Spring Harbor Laboratory (United States), we are interested in measuring the molecular mechanisms that govern the pathological effects of point mutations on the catalytic subunit of the NatA enzyme. The interest in these mutations is that they have been associated with the incidence of rare diseases such as Ogden's syndrome and the creation of animal models that combine these pathologies will enable analysis of therapies for these diseases.

"We have identified small molecules capable of inhibiting the NatB enzyme that may form the basis of a new antitumor and anti-metastatic therapy", Dr. Rafael Aldabe, Principal Investigator.

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Cristina López
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