לוח שנה משולב

Homomers are pervasive protein complexes in most proteomes that involved in all major cellular functions. The three steps in homomer formation are: translation by the ribosome, folding, and assembly into a protein complex. We hypothesize that the relative rates of these three steps are crucial to avoid misassembly in the context of the high nascent chain concentration of the polysome, i.e., the super-complex of multiple translating ribosomes from same mRNA molecule. To examine this, we tested a library of constructs that differ, among other properties, in the N- versus C-terminal position of the assembly (oligomerization) domain. By analyzing the misassembly rates of these constructs in vivo, in vitro and in silico, and by computationally analyzing thousands of native homomers, we show a set of spatiotemporal constraints that act to preserve the integrity of homomers. In conclusion, our results suggest that there has been significant selection in evolution to maintain a balance between translation and assembly.

The mammalian intestine contains trillions of microbes, a community that is dominated by members of the domain Bacteria but also includes members of Archaea, Eukarya, and viruses. The vast repertoire of this microbiome functions in ways that benefit the host. The mucosal immune system co-evolves with the microbiota beginning at birth, acquiring the capacity to tolerate components of the community while maintaining the capacity to respond to invading pathogens. The gut microbiota is shaped and regulated by multiple factors including our genomic composition, the local intestinal niche and multiple environmental factors including our nutritional repertoire and bio-geographical location. Moreover, it has been recently highlighted that dysregulation of these genetic or environmental factors leads to aberrant host-microbiome interactions, ultimately predisposing to pathologies ranging from chronic inflammation, obesity, the metabolic syndrome and even cancer. We have identified various possible mechanisms participating in the reciprocal regulation between the host and the intestinal microbial ecosystem, and demonstrate that disruption of these factors, in mice and humans, lead to dysbiosis and susceptibility to common multi-factorial disease. Understanding the molecular basis of host-microbiome interactions may lead to development of new microbiome-targeting treatments.

Munc13 proteins are key determinants of synaptic vesicle priming and absolutely essential for the completion of the synaptic vesicle cycle at presynaptic active zones. Munc13 function is regulated by three different Ca2+-dependent pathways, and elevations of the presynaptic Ca2+ concentration during neuronal activity leads to a Munc13-dependent increase in the synaptic vesicle priming rate, and consequently to dynamic changes in the efficacy of neurotransmission. I will describe how the Ca2+-dependent regulation of Munc13s affects synaptic signaling in intact circuits, and present the first known synaptopathy caused by a mutation in Munc13-1, which affects a recently discovered interplay between Munc13s, voltage-gated Ca2+ channels, and synaptic vesicle fusogenicity.

Subdiffusion is a hallmark of protein dynamics. Several models predict subdiffusive dynamics, generally either due to some fractional noise or due to trapping dynamics in the underlying energy landscape. However the connection remains unclear, particularly to the underlying energy landscape. We reassess the assumption of a constant single subdiffusive exponent, identifying plateaus in the mean-squared displacement of molecular dynamics trajectories. We associate these with kinetic traps on a minimal model we develop of a hierarchical multibarrier energy landscape, exhibiting a separation of scales in both energy and space. We employ the model to extract the characteristic free energy barriers and length scales associated with the kinetic traps which lead to arrested dynamics. Moreover we identify a second subdiffusive mechanism inherent to the underlying fluctuating process. Lastly we find a relationship between the characteristic energy barriers and the rate of their appea! rance, allowing to reconstruct the effective subdiffusive mean-squared displacement.