Biocurious

/ a biophysics blog

Molecule of the Month: Prions

Posted 3 May 2008 by PhilipJ under

prions

Prions are proteins that can adopt two different forms, a normal form and a misfolded form. This may not seem unusual, since many proteins are flexible and adopt different shapes. However, prions have another unusual characteristic: the misfolded form of the prion can force normal prions to change into the misfolded shape. In this way, a few misfolded prions can corrupt a whole population of normal prions, converting them one-by-one into the misfolded shape. This can have deadly consequences, as the levels of misfolded proteins build up. For instance, misfolding of the PrP prion causes fatal neural diseases in humans and other mammals. To make things worse, misfolded prions are infectious, so a small dose of misfolded prions can infect and corrupt an entire organism.

The normal form of the prion protein PrP (shown here) is found on the surface of nerve cells, but when it changes into its misfolded form, it aggregates into long fibrils that clog up the normal functioning of the brain. Infection occurs when a little bit of the misfolded protein is eaten or accidentally gets into the blood through an injury. A devastating example occurred in a native population in Papua New Guinea, where ritual cannibalism was part of funeral ceremonies. The epidemic probably started when one person developed the disease spontaneously (PrP occasionally adopts the misfolded state all by itself, causing very rare sporadic cases of the disease). Then the misfolded prions spread through the community when the infected person was eaten. More recently, there has been concern that the prions that cause mad cow disease could spread to humans by eating infected meat. The cow PrP protein is very similar to human PrP, and several cases of this type of infection have been seen.

Read the rest at David’s homepage, here.

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Molecule of the Month: Adrenergic receptors

Posted 3 April 2008 by PhilipJ under

Our bodies have many built-in defenses. Our immune system prowls through the body looking for infections by viruses and bacteria. Our blood is filled with molecules that form clots at the first sign of damage. Our nervous system is also hard-wired with instinctive defenses that stand ready to protect us in times of danger. You have probably experienced one of these defenses yourself—when you are startled or scared by an impending danger, you will feel a rush of energy flowing through your body. This has been termed the “flight or fight” response—your body is mobilizing its many resources to make you ready either to run away from danger, or stay and fight.

The small hormone adrenaline, also known as epinephrine, is the messenger that tells cells to ready themselves in danger. It is released into the blood from the adrenal glands, which are situated on top of the kidneys. Then it spreads through the blood to cells throughout the body, where it is sensed by adrenergic receptors on the cell surface. When the adrenergic receptor is stimulated by adrenaline, it passes the message inside the cell to a G-protein. The G-protein then relays the message to a variety of other signaling enzymes, such as adenylyl cyclase, that amplify and spread the message through the cell. To see some of the structures involved in this signaling cascade, take a look at the earlier Molecule of the Month on G-proteins.

Read the rest by David Goodsell here.

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Molecule of the Month: Cadherin

Posted 1 March 2008 by PhilipJ under

cadherin

Your body is composed of trillions of cells, all working together to keep you alive. As you might imagine, this requires a massive infrastructure to hold everything together. This infrastructure is built at many levels. Huge structures, like bones and tendons, are built to support and move the entire body. Many of the spaces between cells are supported by connective tissue, which is built from a collection of sturdy molecular cables and sheets. Finally, an intimate, molecule-sized infrastructure is used to adhere cells directly to their neighbors.

Cadherins are one of the many molecules that glue cells together. They are long proteins that extend from the surface of the cell. The outer portion is composed of a series of folded domains arranged one after the next, and calcium ions bind between each domain, rigidifying the whole structure. If calcium is removed, however, the chain becomes floppy and is easily destroyed by protein-cutting enzymes. The tip of the chain has a special tyrosine amino acid, colored red here, that binds to cadherins on neighboring cells, adhering the two cells together.

For the rest of the story, click here.

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Molecule of the Month: siRNA

Posted 1 February 2008 by PhilipJ under

Double-stranded RNA is often a sign of trouble. Our transfer RNA and ribosomes do contain little hairpins that are double-stranded, but most of the free forms of RNA, messenger RNA molecules in particular, are single strands. Many viruses, however, form long stretches of double-stranded RNA as they replicate their genomes. When our cells find double-stranded RNA, it is often a sign of an infection, and they mount a vigorous response that often leads to death of the entire cell. However, plant and animal cells also have a more targeted defense that attacks the viral RNA directly, termed RNA interference.

RNA interference starts with a long double-stranded RNA, such as the ones formed as viruses replicate. The protein dicer, shown here at the top in blue from PDB entry 2ffl, cuts this RNA into small, distinctive pieces called small interfering RNA (siRNA), shown on the left from PDB entry 2f8s. Each siRNA is about 21 base pairs long and has a distinctive overhang of two base pairs on each strand, and a left-over phosphate at the other end of each strand. This makes them easy to recognize. In the dicer protein, notice how the four manganese ions (in magenta) are arranged. They are thought to make two offset cuts in the RNA double helix, forming the overhang.

Read the rest at David Goodsell’s site, here.

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Molecule of the Month: Circadian Clock Proteins

Posted 1 January 2008 by PhilipJ under

Molecular processes occur so fast that is it difficult to imagine a 24-hour clock that works at the molecular level. But surprisingly, different organisms have evolved many different ways of doing this. Animal cells use a complex collection of proteins (with fanciful names like Clock, Cryptochrome, and Period) that are rhythmically synthesized and degraded each day. The 24-hour oscillation of the levels of these proteins is controlled by a series of interconnected feedback loops, where the levels of the proteins precisely regulates their own production. A much simpler system has been discovered in cyanobacteria. It is composed of three proteins, KaiA, KaiB and KaiC, that together form a circadian clock. At the beginning of the cycle, KaiA (at the top, PDB entry 1r8j) stimulates the large KaiC hexamer (center, PDB entry 2gbl ), which then adds phosphate groups to itself. Then, as KaiC fills itself up with phosphates, it binds to KaiB (bottom, PDB entry 1r5p ), which inactivates KaiA and allows the phosphates to be slowly removed. As the number of phosphates drops, KaiB falls off and KaiA can start the cycle again.

See the rest at David Goodsell’s page, here.

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Molecule of the Month: Oxidosqualene Cyclase

Posted 1 December 2007 by PhilipJ under

Oxydosqualene Cyclase

Cholesterol has gained a bad reputation in recent years. It is absolutely essential in our lives: it is needed to keep our membranes fluid and it is the raw material used to build a host of important molecules such as vitamin D and steroid hormones. However, elevated levels of cholesterol (for instance from a fat-rich diet) have been linked to the formation of atherosclerosis and heart disease. Today, doctors suggest that a combination of a healthy low-fat diet and exercise will keep these two faces of cholesterol in balance.

Cholesterol is a bulky lipid molecule, composed of four linked rings of carbon decorated with hydrogen atoms and a single oxygen atom. A collection of two dozen enzymes is needed to build cholesterol from simple starting compounds. The enzyme shown here, oxidosqualene cyclase (PDB entry 1w6k), performs the most complicated step in this process. It takes a long thin carbon chain, oxidosqualene, and folds it up, creating the four linked rings. The enzyme structure shown here has the final product lanosterol bound in the active site, shown here in white.

Both oxidosqualene and lanosterol are mostly hydrocarbon, and thus are not very soluble in water. The enzyme solves this problem by sticking to the membrane in microsomes inside the cell. It then can pull oxidosqualene directly out of the membrane, and release lanosterol back there. The structure shown here includes several small lipids, shown in purple, bound on the side of the protein that sticks to the membrane. You can also see one of these lipids slipping up into a tunnel that leads into the active site.

More from David Goodsell here.

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