Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

Periodic Report Summary 1 - HOMOMERS (Exploiting homomers to reveal new principles of protein interaction, polymerization and aggregation)

In the protein universe, 30 to 50% of proteins self-assemble in symmetric complexes consisting of multiple copies of identical monomers, called homomers. The widespread nature of homomers in biological systems can be explained on several grounds. This includes their unique geometries (e.g., formation of specific shapes such as viral capsids, channels or barrels), functions (e.g., allosteric regulation) and the ease by which they may evolve (i.e., energetically, self-interacting protein surfaces are on average more favorable than interactions between non-identical surfaces).
An important consequence of forming a homomer is that any mutation occurring at the genetic level is repeated in all the subunits. In the case of homomers with dihedral symmetry (e.g., a dimer of dimers), any mutation necessarily occurs on diametrically opposite subunits. A new interaction on one side is thus also found on the opposite side, leading to the formation of an infinite polymer. This occurs in the sickle-cell disease, where a glutamate-to-valine mutation triggers hemoglobin to self-assemble into filaments.
We considered twelve homomers and asked whether mutations solely increasing surface hydrophobicity could induce de novo self-interactions driving infinite polymerization. Remarkably, polymerization was observed in all twelve homomers, with six forming micrometer-long fibrils in vivo. Biophysical measurements and electron microscopy indicated that mutants self-assembled in their folded states. Though surface mutations are often benign, we revealed their dramatic potential to trigger new interactions and polymerization. This potential suggests a previously underappreciated source of negative selection in protein evolution and can be exploited to engineer artificial protein polymers.
Current efforts dedicated to understanding polymerization and aggregation place an emphasis on protein misfolding. We stress that despite the similarity in terminology, the processes described here differ fundamentally, because polymerization of homomers in filaments and their possible aggregation into fibrils (as for hemoglobin) does not involve amyloids or unfolding of the structure.

The fellow holding the CIG grant has established a research laboratory at the Weizmann Institute of Science, where he holds a tenure-track position. He actively contributes to the academic life of the institute by guiding the research of Master, Ph.D., and post-doctoral students, as well as by teaching two courses.

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