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CURATOR

Postdoctoral Scholar-Employee, University of California, San Diego

PINBOARD SUMMARY

Spontaneous formation and remodeling of synthetic phospholipid membranes

Phospholipids are important natural molecules that can be considered the “bricks” that form the walls of our cells, providing them with structure and protection. Cellular machines called enzymes act as builders who can assemble and modify these building blocks. Just as a homeowner may choose to save money by remodeling an existing home, cells have the ability to modify existing phospholipids instead of making them from scratch. This saves the cell time and energy. Because the cellular components involved in these processes are complex and not entirely understood, we sought to build a tool to recreate phospholipid remodeling in a simplified artificial cell.

To achieve this, we forwent the enzyme builders found in natural cells and instead designed new phospholipid building blocks, which can construct and remodel themselves. This unique strategy allows us to create well-controlled artificial cells, which behave in a similar way to their biological brethren. Having a system like this allows us to reproduce cellular remodeling events and study their effects without the “noise” that is inherent to natural cells. Using this approach, we hope to better understand the changes that occur in cell membranes during specific disease states and with this information, provide insight for the development of more effective drugs to treat these conditions.

We are not only looking forward, however, to the development of new medicines and treatments but also to the past and the rise of complex lifeforms from simple, self-assembling units. A controlled phospholipid remodeling system like this could help to probe standing questions about the emergence of life from simple building blocks. By utilizing this “builderless house” approach, we hope to better understand how life may have arisen in the absence of the enzymatic contractors we know today.

15 ITEMS PINNED

Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins.

Abstract: Synucleins and apolipoproteins have been implicated in a number of membrane and lipid trafficking events. Lipid interaction for both types of proteins is mediated by 11 amino acid repeats that form amphipathic helices. This similarity suggests that synucleins and apolipoproteins might have comparable effects on lipid membranes, but this has not been shown directly. Here, we find that α-synuclein, β-synuclein, and apolipoprotein A-1 have the conserved functional ability to induce membrane curvature and to convert large vesicles into highly curved membrane tubules and vesicles. The resulting structures are morphologically similar to those generated by amphiphysin, a curvature-inducing protein involved in endocytosis. Unlike amphiphysin, however, synucleins and apolipoproteins do not require any scaffolding domains and curvature induction is mediated by the membrane insertion and wedging of amphipathic helices alone. Moreover, we frequently observed that α-synuclein caused membrane structures that had the appearance of nascent budding vesicles. The ability to function as a minimal machinery for vesicle budding agrees well with recent findings that α-synuclein plays a role in vesicle trafficking and enhances endocytosis. Induction of membrane curvature must be under strict regulation in vivo; however, as we find it can also cause disruption of membrane integrity. Because the degree of membrane curvature induction depends on the concerted action of multiple proteins, controlling the local protein density of tubulating proteins may be important. How cellular safeguarding mechanisms prevent such potentially toxic events and whether they go awry in disease remains to be determined.

Pub.: 10 Aug '10, Pinned: 27 Aug '17

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

Abstract: Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.

Pub.: 20 Jul '16, Pinned: 27 Aug '17