Biology subjects

Lyubchenko, Y. L.

Publications and source records attributed to Lyubchenko, Y. L..

3 recordsLinked to original sources

bioRxiv2018

A molecular model of the surface-assisted protein aggregation process

The importance of cell surfaces in the self-assembly of proteins is widely accepted. One biologically significant event is the assembly of amyloidogenic proteins into aggregates, which leads to neurodegenerative disorders like Alzheimers and Parkinsons. The interaction of amyloidogenic proteins with cellular membranes appears to dramatically facilitate the aggregation process. Recent findings indicate that, in the presence of surfaces, aggregation occurs at physiologically low concentrations, suggesting interaction with surfaces plays a critical role in the disease-prone aggregation process. However, the molecular mechanisms behind on-surface aggregation remain unclear. Here we provide a theoretical model that offers a molecular explanation. According to this model, monomers transiently immobilized to surfaces increase the local monomer protein concentration and thus work as nuclei to dramatically accelerate the entire aggregation process. This theory was verified by experimental studies, using mica surfaces, to examine the aggregation kinetics of amyloidogenic-synuclein protein (-Syn) and non-amyloidogenic cytosine deaminase APOBEC3G (A3G).

biophysics↗

bioRxiv2018

Phospholipid membranes promote the early stage assembly of α-synuclein aggregates

Development of Parkinsons disease is associated with spontaneous self-assembly of -synuclein (-syn). Efforts aimed at understanding this process have produced little clarity and the mechanism remains elusive. We report a novel effect of phospholipid bilayers on the catalysis of -syn aggregation from monomers. We directly visualized -syn aggregation on supported lipid bilayers using time-lapse atomic force microscopy. We discovered that -syn assemble in aggregates on bilayer surfaces even at the nanomolar concentration of monomers in solution. The efficiency of the aggregation process depends on the membrane composition, being highest for a negatively charged bilayer. Furthermore, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation can be a mechanism by which pathological aggregates are produced. Computational modeling revealed that interaction of -syn with bilayer surface changes the protein conformation and its affinity to assemble into dimers, and these properties depend on the bilayer composition. A model of the membrane-mediated aggregation triggering the assembly of neurotoxic aggregates is proposed.

neuroscience↗

bioRxiv2017

Nanoscale Dynamics of Centromere Nucleosomes and the Critical Roles of CENP-A

In the absence of a functioning centromere, chromosome segregation becomes aberrant, leading to an increased rate of aneuploidy. The highly specific recognition of centromeres by kinetochores suggests that specific structural characteristics define this region, however, the structural details and mechanism underlying this recognition remains a matter of intense investigation. To address this, High speed atomic force microscopy was used for direct visualization of the spontaneous dynamics of CENP-A nucleosomes at the sub-second time scale. We report that CENP-A nucleosomes change conformation spontaneously and reversibly, utilizing two major pathways: unwrapping, and looping of the DNA; enabling core transfer between neighboring DNA substrates. Along with these nucleosome dynamics we observed that CENP-A stabilizes the histone core against dissociating to histone subunits, unique from H3 cores which are only capable of such plasticity in the presence of remodeling factors. These findings have implications for the dynamics and integrity of nucleosomes at the centromere.

biophysics↗