Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Monday Speaker Abstracts

MEMBRANE REMODELING BY THE COLLECTIVE ACTION OF CAVEOLIN-1 Korbinian Liebl 1,2 ; Gregory A Voth 1 ; 1 University of Chicago, Chicago, IL, USA 2 SISSA, Trieste, Italy Caveolin-1 (CAV-1) are membrane-remodeling proteins that consist of 178 amino acids. Multiple CAV-1 protomers can oligomerize into the 8S-complex that represents a disk-like structure (~14 nm diameter) with a central beta-barrel. These complexes exhibit a monotopic arrangement (inserted in only one membrane leaflet) and through higher-order interactions remodel composition and shape of the membrane, a process that is critically implicated in many cellular processes, e.g., caveolae biogenesis. The mechanistic and cooperative functioning of these CAV-1 8S complexes, however, has remained elusive. To address this shortcoming, we have performed 1µs long atomistic MD simulations that gave new insight into membrane remodeling mechanisms by this complex. For instance, we have found that the beta-barrel can store and extract cholesterol from the membrane and that post-translational modifications enhance cholesterol accumulation by the entire complex. To address the open large-scale questions and noticing that custom top-down coarse-grained (CG) models may lead to an unphysical description of this complex, we have developed a new bottom-up CG model that captures the binding of the complex in the membrane as well as relevant membrane properties correctly. In this presentation, I will present the result of the parameterization of such a CG model that facilitates significant length scaling beyond 100nm. Large-scale simulations with this model show cooperative membrane bending due to stress-amplification by proximate CAV1-8S complexes. In addition, we also monitor that distinct complexes can bind to each other, hence promoting cluster formation. We further show that such clusters scaffold ~70nm broad membrane invaginations, and additional cofactors are needed for further restriction and budding.

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