Molecular Mechanism of ACAP1 Proteins Binding to Cell Membrane

Description

This project proposes a combined computational and experimental investigation of themolecular mechanism of interactions between ACAP1 proteins and the membrane.Protein-membrane interaction is crucial to many essential cellular processes, some ofwhich are key pathogenic factors in a number of human diseases including cancer,Alzheimer’s disease, diabetes mellitus, mental retardation and epilepsy.Numerous transportation carriers accurately and efficiently deliver molecules to desireddestinations in order for cells to maintain functions such as signaling, sorting,autophagy, membrane trafficking, organelle motility and so on. These carriers aregenerated by complicated protein-membrane interactions. The Bin-Amphiphysin-Rvs(BAR) superfamily proteins are one group of regulator proteins that remodel cellmembranes via two well-known mechanisms, i.e., scaffolding and wedging mechanisms.However, a novel mechanism different than these two mechanisms has been reported inArfgap with Coil coil, Ankyrin repeat, and Pleckstrin Homology domain protein 1(ACAP1) protein-membrane systems where the BAR domains do not directly interactwith the membrane as they do in other BAR domain containing proteins (BAR proteins).The ACAP1 protein instead unexpectedly binds to the membrane asymmetrically usingonly one of its Pleckstrin Homology (PH) domains. The molecular mechanism throughwhich the ACAP1 proteins interact with the membrane to induce membrane deformationis still unclear.In this proposal, we will first computationally investigate the interactions betweenACAP1 proteins and the membrane. Specifically, since the PH domain binds to themembrane, we will quantify the binding affinity of the PH domain to different lipidmolecules. Next, we will formulate a protein-membrane interaction potential to describethe protein-membrane system and search for the optimal binding orientation of theprotein. To speed up the search, ACAP1 proteins will be coarse-grained and a programusing the Monte Carlo method will be developed. Finally, our experimental collaboratorwill carry out cryo-electron microscopy (EM) reconstruction experiments to verify thecomputational predictions.The proposed computational approach enables a systematic investigation of ACAP1protein – membrane interactions for the first time. The results will provide newinsights into the molecular mechanism of interactions between ACAP1 protein and themembrane. The newly developed protein-membrane interaction potential is applicable toother protein-surface adsorption questions. It will be useful in the effort to designsurfaces to attract enzymes or antibodies for biomedical applications. Our explorationwill also shed light on designing new drugs for the aforementioned diseases.