11:36am Tuesday 24 October 2017

Discovered a new regulatory mechanism of c-Src, the human protein bound to the oldest known oncogene


The c-Src protein is the cellular form associated to the first oncogene (a mutant protein which turns healthy cells into carcinogenic ones) discovered in the Rous sarcoma virus more than one hundred years ago and which has been extensively studied since the 1980s. The oncogenic character of c-Src results mainly from incorrect regulation of this protein. A research, led by UB professor Miquel Pons that has been just published on Scientific Reports, has discovered a new regulation region of this protein that, when modified, can affect the survival of the cell.


According to Miquel Pons, leader of the Biomolecular Nuclear Magnetic Resonance (NMR) Research Group, affiliated with the Department of Organic Chemistry of the UB, “the discovery of a new regulatory mechanism in such a relevant and extensively studied protein proves the importance of original approaches based on molecular structure to find new biological activities and suggest new strategies in the fight against cancer”.

The work, carried out in vitro and in vivo, analysed the role of the so-called Unique domain, an often overlooked region where the largest variations among proteins of the same family are found. The in vivo studies used Xenopus laevis oocytes as a model system. The large size of these cells allows the injection of RNA encoding c-Src protein, or RNA with a mutant Unique domain of the c-Src protein.

It was observed that wild-type c-Src protein produced an acceleration of oocytes maturation, but in the case of the mutant protein, the majority of oocytes died. These observations highlight “the biological relevance of c-Src Unique domain interactions and suggest that it could be possible to control c-Src, so that its activation, instead of triggering the transformation of healthy cells into carcinogenic ones, would cause in their death, before they develop their pathogenic potential”, concludes the researcher.

NMR techniques, essential for this research. were carried out in the Singular Scientific and Technological Facility of the University of Barcelona, located at the Barcelona Science Park (PCB). Margarida Gairí, from the Scientific and Technological Centers of the UB, and some researchers from the IRB also participated in the study. All participating groups are affiliated with the Barcelona Knowledge Campus, a campus of international excellence.


Disordered proteins: the unknown part of the genome

From a structural point of view, c-Src protein contains folded and unfolded regions. The Unique domain is a disordered region. A widespread notion is that folded proteins are functional, whereas unfolding results in a loss of activity. “But, it is not always like that”, affirms Pons. The sequence of the human genome revealed that only about a third of human proteins are folded. In contrast, a third of the eukaryotic proteins are mostly disordered in their native state, and the remaining third, are proteins in which the two types of regions (folded and unfolded) co-exist. c-Src belongs to this class. Considering that 80 % of the proteins related to cancer have disordered regions, it is evident that “these regions are relevant for the correct activity of certain proteins which ensure a well-coordinated growth of individual cells in healthy tissues, but which can cause the development of cancers when they become deregulated”, explains the expert. “The discovery of disordered proteins is quite recent, so up to now they have been hardly studied”, remarks Pons.

c-Src protein is anchored to cell membrane surfaces through one end of the Unique domain. The folded part is attached at the other end. The folded part contains the active domain responsible for the enzymatic activity of c-Src that modifies other proteins, and thus controls the transfer of information across the cell. “We suggest that the secondary lipid interactions involving the Unique domain that we have discovered contribute to locate the c-Src “war-head” at the proper distance from the membrane and thus change the repertoire of molecules that are modified by c-Src and the pathway through which the information is transferred, like in a railway point. We have already discovered several interactions that can change this path”, says Pons.

Yolanda Pérez, Mariano Maffei, Ana Igea, Irene Amata, Margarida Gairí, Angel R. Nebreda, Pau Bernadó and Miquel Pons. “Lipid binding by the Unique and SH3 domains of c-Src suggest a new regulatory mechanism“. Scientific Reports, 18th February 2013. Doi: 10.1038/srep01295
Universitat de Barcelona

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