Homomers · Exploiting homomers to reveal new principles of protein interaction, polymerization and aggregation
FP7 — People (Marie Curie Actions)
- Duration
- 2013-12-01 → 2017-11-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
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.
Data: CORDIS, © European Union
Project objective
In the protein universe, 30 to 50% of proteins self-assemble to form symmetrical complexes consisting of multiple copies of themselves, called homomers. A peculiarity of homomers is that any mutation is necessarily repeated in all subunits. In a symmetric dimer for example, any mutation of one copy is also found in the second identical copy. Depending where the mutation occurs on the surface, the repetitions of the mutation may or may not be “synergistic”, i.e., participate together to the formation of a new self-interaction. We propose that the consequences of a mutation depend mainly on two factors: (i) its location on the homomer’s surface, which influences its synergy and (ii) the symmetry type of the homomer. We anticipate that these two factors are tightly coupled to the probability that a random mutation triggers the infinite polymerization and aggregation of a homomer. We thus propose a two-pronged approach to analyze this question. (i) In silico, using homomers of known three-dimensional structure, we will infer a “risk factor” for every surface residue, reflecting its probability to be associated with polymerization. We anticipate that high-risk residues are, together with their environment, under pressure to avoid un-wanted interactions. We also anticipate those sites to be under stronger evolutionary constraints. (ii) In vivo, we will artificially introduce amino acid substitutions in homomers at sites that are at high or low-risk, and quantify the potential of these mutations to trigger aggregation or polymerization of the homomer. This project, which combines both theoretical and experimental biology, will help us unveil new basic physico-chemical properties of proteins and of their potential to form unwanted aggregates in cells. This knowledge will contribute to our better understanding of important diseases involving uncontrolled self-association of proteins, such as Parkinson’s, Alzheimer’s, Huntingdon’s, or the sickle cell disease.
Original text from CORDIS.
Participants
- WEIZMANN INSTITUTE OF SCIENCE · RehovotCoordinatorIsrael
Links
Data: CORDIS, © European Union