Biocurious

/ a biophysics blog

Molecule of the Month: Vaults

Posted 6 June 2009 by PhilipJ under

Vaults

Our cells are filled with compartments, each performing a specific function. Some of these compartments, such as mitochondria and lysozomes, are very large and enclose many different molecular machines. Other intracellular compartments are smaller, such as the transport vesicles that shuttle proteins from site to site inside the cell. Most of these compartments, including mitochondria, lysozomes and transport vesicles, are surrounded by membranes. However, in special cases, cells build smaller compartments surrounded by a protein shell. In our own cells, vaults are a spectacular example of these protein-enclosed compartments.

Vaults are composed of many copies of the major vault protein, which assembles to form a hollow football-shaped shell. The one shown here is from rat liver cells (PDB entries 2zuo, 2zv4, and 2zv5) and contains 78 copies of the protein. Inside cells, the vault also encloses a few other molecules, which were not seen in the crystal structure because they don’t have a symmetrical structure inside the vault. These molecules include several small RNA molecules, a protein that binds to RNA, and an enzyme that adds nucleotides to proteins.

Read more by David Goodsell at the RCSB PDB here.

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Molecule of the Month: Influenza Neuraminidase

Posted 13 May 2009 by PhilipJ under

influenza neuraminidaseInfluenza virus is continually changing and every decade or so, a dangerous new strain appears and poses a threat to public health. This year, there has been an outbreak of a new strain of H1N1 flu, more commonly known as swine flu. The H1N1 designation refers to the two molecules that cover the surface of the virus: hemagglutinin and neuraminidase. Together, these two molecules control the infectivity of the virus. Hemagglutinin plays the starring role as the virus approaches a cell, binding to polysaccharide chains on the cell surface and then injecting the viral genome into the cell. Neuraminidase, on the other hand, plays its major role after the virus leaves an infected cell. It ensures that the virus doesn’t get stuck on the cell surface by clipping off the ends of these polysaccharide chains.

Neuraminidase, shown here at the top from PDB entry 1nn2, is composed of four identical subunits arranged in a square. It is normally attached to the virus surface through a long protein stalk (not shown). The active sites are in a deep depression on the upper surface. They bind to polysaccharide chains and clip off the sugars at the end. The surface of neuraminidase is decorated with several polysaccharide chains (seen extending upwards and downwards in this structure) that are similar to the polysaccharide chains that decorate our own cell surface proteins.

As with hemagglutinin, neuraminidase comes in a variety of subtypes named N1-N9. These subtypes are defined by their interaction with antibodies: all of the variants within a given subtype will be neutralized by a similar set of antibodies. These subtypes are one of the causes of the continual effectiveness of influenza. Some of the subtypes promote infection in people, others promote infection in birds, and others target pigs and other mammals. As viruses spread and infect different organisms, they can mix and match different subtypes, randomly building new combinations and occasionally coming up with particularly lethal combinations.

To read more about this timely molecule of the month, click here for the rest by David Goodsell at the RCSB PDB.

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Molecule of the Month: Oct and Sox Transcription Factors

Posted 14 April 2009 by PhilipJ under

Oct&Sox

The development of a complete human being from a single cell is one of the great miracles of life. A human egg cell contains about 30,000 genes that encode proteins, and of these, about 3,000 of these genes encode transcription factors. Transcription factors determine when genes will be turned on and turned off, orchestrating the many processes involved in the development of an embryo and the many tasks performed by each cell after a child is born. Amazingly, there is only about 1 transcription factor for every 10 genes, posing a puzzle: how does this limited set of proteins control the many genes and processes that must be regulated?

One of the answers to this question may be discovered by looking at the binding sites for transcription factors in the genome. Typical genes in our cells have extensive regulatory regions before and after the genes, sometimes 100,000 base pairs away, and occasionally even inside the genes. These regions act in many different ways, as enhancers, silencers, insulators, and promotors of the gene. Each gene is controlled by a combination of many transcription factors, which together form a consensus as to whether the gene will be expressed or not at any given time.

Oct4 and its cofactor Sox2 are at the center of a collection of transcription factors that control the first decisions in the development of an embryo. Oct4 is present in embryonic stem cells, and its levels drop when the cell starts to divide and differentiate into different types of cells. It has been called the “gatekeeper” of development, since it is necessary for maintaining the stem cell state. The structure shown here, from PDB entry 1gt0, shows the DNA-binding portions of a similar protein, Oct1 (at the bottom in turquoise), and Sox2 (at the top in blue) bound to a short piece of DNA (in orange and pink).

Read the rest from David Goodsell at the RCSB PDB here.

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Molecule of the Month: Hydrogenase

Posted 6 March 2009 by PhilipJ under

Hydrogenase

Hydrogen gas is an unusual substance. Normally, it is stable and must be coaxed with powerful catalysts to enter into chemical reactions. But when mixed with oxygen, a tiny spark will set off an explosive chain reaction. Hydrogen gas holds great promise to be the greenest of green energy sources. It has many advantages: compared with many fuels, it releases a lot of energy for its weight, and the reaction forms only energy and pure water. It has substantial disadvantages, however. It is dangerous to store, and it is difficult to perform the reaction in a controlled, non-explosive manner. Currently, the fuel cells being developed for use in hydrogen-powered vehicles use costly platinum catalysts to perform this reaction. Researchers are now looking to nature for other alternatives.

Enzymes that split hydrogen gas have evolved at least three separate times in the history of life on the Earth. These enzymes are used either to split hydrogen gas for use as energy, or to create hydrogen gas as a product of their reaction. Three examples are shown here. At the top is a nickel-iron hydrogenase (PDB entry 2frv), in the center is an iron-iron hydrogenase (PDB entry 1feh), and at the bottom is an iron hydrogenase (PDB entry 3dag and 3f47). As the names imply, all of them use metal ions in their reactions.

Read the rest by David Goodsell at the RCSB PDB

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Molecule of the Month: Auxin and TIR1 Ubiquitin Ligase

Posted 11 February 2009 by PhilipJ under

Auxin and TIR1 Ubiquitin Ligase

Plants, like animals, have hormones that deliver chemical messages between distant cells. Charles Darwin and his son discovered this over a century ago—they noticed that if they shined a light on the tips of grass shoots, the stems bend to bring the entire shoot towards the light. Somehow, a message was being sent from the tip down to the stem. You might also have observed the action of hormonal signals in plants: when you prune a tree to make it more bushy, you are modifying the traffic of plant hormones. Both of these effects are caused by the phytohormone auxin.

Auxin is made by cells in the tips of plants, and then it is transported throughout the rest of the plant. It is essential for life of the plant, and the plant quickly dies if deprived of it. Auxin controls many functions, including proper patterning of leaves on stems and response to light and gravity. For instance, auxin controls the branching of plants. When you cut off the tip of a growing plant, you remove the major source of auxin, and the resulting lower levels of auxin cause the remaining parts to branch out instead of growing straight up.

The ultimate effect of auxin is to regulate a collection of genes involved in cell division, elongation and differentiation. However, auxin does not appear to act directly on repressors or activators of these genes—it uses a more circuitous mechanism. Instead, auxin binds to a class of ubiquitin ligases, such as the TIR1 ubiquitin ligase shown here from PDB entry 2p1p. These enzymes assist with the destruction of proteins by the ubiquitin/proteasome system. Auxin binds to the ligase and promotes the ubiquitination of a series of regulatory proteins, termed Aux/IAA proteins. When these are destroyed, they allow a series of auxin response factors (ARF) to interact directly with the genes.

For more on this molecule, read the rest from David Goodsell at the RCSB PDB.

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Molecule of the Month: Tobacco Mosaic Virus

Posted 7 January 2009 by PhilipJ under

TMV

Tobacco mosaic virus (TMV) has been at the center of virus research since its discovery over a hundred years ago. TMV was the first virus to be discovered. Late in the 19th century, researchers found that a tiny infectious agent, too small to be a bacterium, was the cause of a disease of tobacco plants. It then took 30 years of work before the nature of this mysterious agent became apparent. In a Nobel-prize-winning study, Wendell Stanley coaxed the virus to form crystals, and discovered that it was composed primarily of protein. Others quickly discovered that there was also RNA in the virus. Then, many prominent structural researchers (including J. D. Bernal, Rosalind Franklin, Ken Holmes, Aaron Klug, Don Caspar, and Gerald Stubbs) used X-ray diffraction and electron microscopy to probe the structure of the virus.

Several structures of the whole tobacco mosaic virus are available in the PDB, including one solved by x-ray diffraction of fibrous crystals (shown here from PDB entry 2tmv) and a more recent structure solved by analysis of many electron micrographs (PDB entry 2om3). The virus is composed of one strand of RNA (shown in red) wrapped inside a sheath of protein (shown in blue). The protein coat is composed of about 2130 copies of a small protein, which stack like bricks in a cylindrical chimney. The RNA strand encodes four proteins, which together orchestrate the life cycle of the virus. These include two proteins that replicate the viral RNA, a protein that transports the RNA from cell to cell, spreading the infection, and the capsid protein seen in the PDB structures.

Read the rest from David Goodsell at the RCSB PDB, here.

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