This article was contributed by Tina Liu
Interior design of the cell
A cell must complete many tasks to survive and multiply – it must duplicate its genetic material, absorb nutrients, sense its surroundings, and regulate its growth to match the available resources. Complex, or “eukaryotic”, cells use compartments called organelles to help carry out many of these functions. The organelles of a cell are akin to the rooms of a house. Just as a kitchen is for cooking and bedrooms are for sleeping, distinct organelles are host to different cellular events, too. This division of labor enables cells to complete tasks more efficiently and supports the complexity of higher organisms like animals and plants.
Organelles are important in keeping different processes from getting mixed up with each other. Think of it this way – you would never keep your pots and pans in the bathroom if you wished to be an efficient cook. Similarly, a cell must keep its contents organized to function efficiently. Each organelle therefore is enveloped by a membrane – a double layer of fats that acts like a wall to prevent inappropriate mixing or movement of certain molecules. Unlike the plaster walls that separate rooms, though, the membranes of organelles are bendable, allowing them to come in diverse shapes and sizes: wobbly ovals, long cylinders, flattened sheets and more.
One question that intrigues scientists is how these distinct shapes, or morphologies, are generated and maintained. There could be several answers to this question. We know that these organelle membranes are made of different types of fat molecules. Since different types of fat molecules possess different shapes, changing the exact combination of fats in a membrane can change the membrane’s curvature. A second way that membranes can be deformed is through proteins – large molecular machines that interact with and manipulate other molecules. Proteins can alter the shape of certain fat molecules or move them around to change membrane curvature. They can also directly pull or push on a region of the membrane to bend it. For example, some proteins can take hold of the membrane and draw it out into thin, hollow tubes. This particular strategy is a way in which the endoplasmic reticulum, an organelle involved in secretion, acquires its tubular shape.
The endoplasmic reticulum, or ER, is an organelle that possesses a number of long, hollow, membranous tubes that scientists refer to as “tubules.” Numerous three-way junctions connect the tubules, giving the ER a net-like appearance. What are the proteins that generate this tubular “ER network”? Two classes of proteins – reticulon and DP1 family proteins – have thus far been identified as tubule-forming factors. When proteins from either of these two classes are removed from cells, the ER loses its tubular appearance. Even more remarkably, when researchers obtained purified reticulon/DP1 proteins and mixed them with fat molecules in a test tube, long tubules – resembling those inside cells – assembled spontaneously. However, the factor that joins the tubes together to create the observed network has yet to be determined. Recent studies now indicate that a different class of proteins called atlastins may be the missing piece in this puzzle.
Atlastins: Making Membranes Meet
Membranes are ubiquitous in biology – they are found covering the exterior surfaces of cells, organelles, and even virus particles. One important property of membranes is that they must be able to grow or shrink in size, based on whether cells are growing, dividing, or moving around. To meet this challenge, the cell makes proteins that can break down or join together membranes. A clue that atlastins may be the fusing factors of the ER came from experiments that demonstrated that the removal of atlastins from neurons led to the fragmentation of the ER. Furthermore, investigators observed that introduction of certain mutant, or improperly made, variants of atlastin into cells caused ER tubules to become long and unbranched.
Recently, research groups from the United States and Italy teamed up to study the fusing capability of atlastins. In order to mimic the cellular environment, they embedded purified atlastin proteins in membrane vesicles – hollow spheres of fat molecules derived from the ER. To test the extent to which atlastin induced vesicle fusion, they used a technique called fluorescence resonance energy fransfer (FRET). This technology can be used to monitor small changes in distance between specific pairs of fluorescent molecules. These investigators mixed a set of vesicles that was coated, or “labeled,” with fluorescent molecules with a set that was unlabeled. They reasoned that the fluorescent molecule pairs would tend to be farther from each other on a large, fused vesicle versus a smaller, un-fused vesicle. These experiments proved for the first time that atlastins can fuse ER membranes, suggesting that they could be the key factors in forming the three-way junctions of the ER.
The Shape of Things to Come
The discovery of atlastins as a means for shaping the ER is a major step for understanding how cells are built, from the inside out. However, many questions about how atlastins work still remain unanswered. Are atlastins the only protein family that fuses ER membranes inside cells? Many different variants of atlastin proteins are produced in different cell types – what might be the role of these different isoforms? Atlastins have also been shown to interact with other membrane proteins, including the tubule-forming proteins. How might atlastin cooperate with these other molecular machines?
Studying atlastins may also aid in developing a treatment for hereditary spastic paraplegia (HSP), an inherited neurological disease. Mutations, or improper changes, in atlastin are one of the chief causes of this disorder. In individuals suffering from HSP, the longest nerve fibers of the spinal cord degenerate, preventing the transmission of impulses from the brain to the lower extremities. As a result, patients experience weakness and muscle spasms in their legs, which can prevent them from walking normally. Why is it that cells in the longest nerve fibers are the primary victims of these atlastin mutations? Perhaps these neural cells require the ER to assume a particular shape in order to span the distance from the brain to the lower parts of the spinal cord. To determine if this is the case and to obtain a more detailed picture of atlastin function, additional studies are still required.
For more information, please see:
Little-known Protein Found To Be Key Player in Building and Maintaining Healthy Cells. Rice University. Science Daily. 07/30/2009. <http://www.sciencedaily.com/releases/2009/07/090729121607.htm>
The Birth of Complex Cells. Christian de Duve. Scientific American. April 1996. <http://www2.ignatius.edu/faculty/bogen/SciAmArticles/Complex%20cells.pdf>
Primary research referenced in this article:
Homotypic fusion of ER membranes requires the dynamin-like GTPase Atlastin. Orso G, Pendin D, Liu S, Tosetto J, Moss TJ, Faust JE, Micaroni M, Egorova A, Martinuzzi A, McNew JA, Daga A. Nature. 2009 Aug 20;460(7258):978-83. Epub 2009 Jul 26.
A class of dynamin-like GTPases involved in the generation of the tubular ER network. Hu J, Shibata Y, Zhu PP, Voss C, Rismanchi N, Prinz WA, Rapoport TA, Blackstone C. Cell. 2009 Aug 7;138(3):549-61.
Membrane proteins of the endoplasmic reticulum induce high-curvature tubules. Hu J, Shibata Y, Voss C, Shemesh T, Li Z, Coughlin M, Kozlov MM, Rapoport TA, Prinz WA. Science. 2008 Feb 29;319(5867):1247-50.
A class of membrane proteins shaping the tubular endoplasmic reticulum. Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. Cell. 2006 Feb 10;124(3):573-86. Erratum in: Cell. 2007 Aug 24;130(4):754.