In the name of scientific accuracy, author Tina Liu wishes to post a corrected version of last month’s post, ‘Keeping in shape: the morphology of internal cellular structures‘.  For tags and references, please see the original version of this article, here.

Corrected Version: Keeping in shape: the morphology of internal cellular structures

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, different organelles host different cellular events.  This division of labor allows cells to complete tasks efficiently and supports the complexity of higher organisms like plants and animals.

Every organelle in the cell is enveloped by a membrane – a double layer of fat-like molecules that prevents the contents of an organelle from escaping.  Why is it so important to the cell to prevent a random flow of materials between organelles?  Well, think of it this way.  You would never keep your clothing on the stove or your toilet paper in the bedroom.  Why?  Because it would make everyday activities inconvenient.  Likewise, mixing molecules from different organelles can cause the cell to run less efficiently.  The membranes of organelles are thus vital in preserving the fitness of the cell.

Curvy membranes

Unlike the walls of a house, the organelle membranes are bendable, allowing them to come in diverse shapes and sizes: wobbly ovals, long cylinders, flattened sheets and more.  A 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 organelle membranes are mainly composed of  phospholipids, a class of molecules related to those in fats and oils.  Different types of phospholipids have different shapes, so changing the amount of each type of phospholipid in a membrane can change the membrane’s shape.  A second way that membranes can be deformed is through proteins – large molecular machines that interact with and manipulate other molecules.  Proteins can modify parts of a phospholipid molecule to change its shape or move around specific types of phospholipids to change the membrane’s composition.  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.  In fact, this is one way in which the endoplasmic reticulum, an organelle involved in the biosynthesis and secretion of many biological molecules, 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 membrane lipids in a test tube, long tubules – resembling those inside cells – assembled spontaneously.  However, the factor that joins the tubes together to create the branched 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 has proteins that can break apart or fuse membranes.  A clue that atlastins may be the membrane-fusing machines of the ER network came from experiments that demonstrated that the removal of atlastins from neurons led to the fragmentation of the ER.  Furthermore, a role for atlastins in connecting tubules was suggested by the observation that introducing mutant, or improperly made, variants of atlastin caused the appearance of long, unbranched ER tubules in cells.

Research groups from the United States and Italy teamed up to determine whether atlastins were indeed capable of membrane fusion.  To model the cellular situation, they embedded purified atlastin proteins in liposomes – hollow, spherical structures made from fat-like molecules.  Liposomes can be thought of as artificial organelles, since they are also enveloped by a double layer of fat-like molecules.  The investigators found that when atlastins were embedded in the liposome “membranes” and provided with a source of energy, liposome fusion occurred.  These were the first experiments that provided evidence of an intrinsic membrane-fusing capability in atlastins, and the results support the hypothesis that atlastins join ER tubules together.  However, much still remains to be known about how atlastins can bring membranes together and what other molecules they might need to create the extensive network of ER tubules seen in cells.

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.

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