Protein self-assembly is a major public health issue, but these mechanisms are still poorly understood. Researchers at the Weizmann Institute have made progress in understanding this well-kept secret of the human body, which leads to diseases such as diabetes and Alzheimer's.
The functions of the human body are carried out by large molecules of great complexity, called proteins. For example, the storage of oxygen in our blood is ensured by hemoglobin, a protein. The structure and dynamics of these proteins are absolutely essential for the proper functioning of our body which, in contact with the outside world, undergoes many mutations. In the vast majority of cases, they are either benign or temporary, because our body manages to destroy these mutations. But sometimes a mutation outlives our myriad body defense systems and takes hold. In the case of Alzheimer's disease, mutated proteins begin to clump together and cause the symptoms we know.
Dr. Emmanuel Levy and his team are interested in the ability of proteins to self-assemble with each other. Inspired by the hemoglobin protein, known for its capacity for self-assembly in the genetic disease of sickle cell disease, they attempted to understand the criteria for self-assembly of proteins.
They show the importance of interfacial symmetry: if in addition to its symmetry capacities, the protein has groups inclined to form a bond, the proteins will begin to form longer and longer filaments, over the course of self- assembly.
Take the two examples mentioned above – sickle cell anemia and Alzheimer's disease. In the first case, hemoglobin proteins can assemble naturally, without changing shape for self-assembly. In the case of Alzheimer's disease, proteins have to change shape, which takes time and energy, which partly explains the slow progression of the disease.
In their experiments, the researchers made a protein made up of eight identical units. By this property, the mutation of a gene produces eight identical mutations in each of the units of the protein. After multiple trials, they finally found a unique mutation allowing to create large filaments, adding hydrophobic amino acids to the surface (ie which do not like water). Wanting to continue their studies in a broader framework, they selected eleven symmetrical proteins and created seventy-three different mutations in each of them. This titanic work shows that, in thirty cases, mutations allow proteins to self-assemble. In half of the cases, the proteins assemble into filaments, in the other half, they form amorphous lumps.
If these mutations are so easy to produce, why are they so rare in nature? The researchers observe that, in general, proteins with high symmetry have hydrophilic amino acids on their surface, which limits inter-protein interactions. Indeed, the hydrophilic nature 'attracts' water molecules, thus limiting interactions with other proteins.
These researchers are part of a large community trying to understand the self-assembly of proteins, which is a major public health issue for diseases such as Alzheimer's or diabetes. This research also makes it possible to advance in the understanding and control of the nano world as a whole, that is to say a world 100 times smaller than the smallest grain of sand.
Author: Samuel Cousin, post-doctoral fellow at the Institute Weizmann science for BVST
Posted in Nature, August 2 2017
