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Researchers decipher structure of a human protease implicated in various diseases

Modifications in proteins after they are synthesized (post-translational) are changes that play a fundamental role in cell regulation, as they can alter biological activity and influence various physiological processes. There are many types, including SUMOylation, a mechanism in which the SUMO (Small Ubiquitin-like MOdifier) protein binds to other proteins and modulates their functions.

It is a complex process with a large number of proteins involved: both those necessary for SUMO activation and those that are the target of the modification. The SUMO proteases stand out specifically, and are responsible for activating the SUMO molecule, as well as for processing and removing its binding from the target proteins.

New research led by the Institute of Biotechnology and Biomedicine of the UAB (IBB-UAB) carried out the structural characterization of the human protease SENP5, implicated in several diseases, with the aim of identifying the key residues for the discrimination and specificity of this protease with respect to the different types of SUMO. The study is in the journal Nature Communications.

The team presented the three-dimensional structure of SENP5 in complex with different types of SUMO. The results of the analysis of the different complexes reveal a positively charged region that is directly involved in the preference of SENP5 for SUMO2. The structural characterization made it possible to define the key contacts of SENP5 with SUMO2. This opens the way for further research and the design of possible specific inhibitors for this protease.

"The human SENP family plays a fundamental role in the regulation of a variety of cell processes, and its deregulation is involved in many diseases, such as cancer, neurodegenerative disorders and cardiovascular diseases," explains UAB researcher David Reverter, coordinator of the research. "The results we have obtained could facilitate the development of highly specific inhibitors aimed at individual members of the protein family studied, offering new therapeutic opportunities with minimal side effects."