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The example shown here is alpha1-antitrypsin, from PDB entry 1psi. It is found in the bloodstream, where it protects the surrounding tissues from the protein-cutting enzyme elastase.

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Neutrophils a type of white blood cell secrete elastase in sites of inflammation, where it breaks down connective tissue and allows blood cells to enter and do their jobs in defense and repair. The serpin protects the neighboring areas and ensures that the elastase doesn't spread throughout the body. Serpins are molecular mouse traps, complete with bait and a swinging arm.

They are metastable proteins, meaning that they are only partially stable in their active form, but they can snap into a far more stable form when they find a protease. The key is a flexible loop, shown here in magenta. One amino acid in this loop is used as bait. In alpha1-antitrypsin, it is a methionine, shown here in red and orange. As shown on the next two pages, proteases are trapped and destroyed when they take this bait. Over thirty different human serpins a number of which are available in the PDB have been studied, each with a different essential job.

Many are found in the blood. Several control the process of blood clotting: antithrombin limits the action of thrombin when a clot is forming, and antiplasmin limits the action of plasmin when blood clots are being disassembled.

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  • Summary: Serpin (serine protease inhibitor).
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Other serpins control the action of proteases used in the complement system, which protects us from bacterial infection. For a description of this diverse family of molecules, take a look at the Protein of the Month at the European Bioinformatics Institute.

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When serpins fail, they can cause serious problems. Two types of problems often occur.

A serpin can be defective, so that it is unable to block its proper target and leaves the protease to go on a rampage. This happens in emphysema, where alpha1-antitrypsin is compromised and elastase destroys connective tissue in the lungs. One way that the serpin can be disabled is through smoking, which can modify the methionine amino acid used as bait. Alternatively, the unique trapping mechanism of serpins, shown in more detail on the following pages, can lead to another problem. After the loop is broken, it can associate with other copies of the serpin, leading to bulky aggregates.

If these form inside nerve cells, they can block nerve function and lead to dementia. Action of alpha 1-antitrypsin, with trypsin in green. The flexible loop of serpins, known as the reactive center loop, is the bait and trap. The protease, shown here in green, binds to the bait and begins to perform its normal cleavage reaction.

The structure on the left, from PDB entry 1k9o , shows trypsin just after it binds.

Chemistry and Biology of Serpins | SpringerLink

The reactive serine in the protease attacks the loop, forms a bond with the chain, and makes the break. Normally, a water molecule would then be used to release the protease from its target. But instead, the serpin takes control before the unlucky trypsin can extricate itself.

The flexible loop, now cleaved and free to move, zips into a comfortable groove in the side of the serpin, dragging the protease all the way to the other side, as shown in the structure on the right, from PDB entry 1ezx. You might think that the trypsin could then perform the rest of its reaction and release itself. But the strand of the serpin, now gripped firmly in the groove on its side, is just a few amino acids too short, so the trypsin is jammed up against the bottom of the serpin. This pulls the active site of trypsin out of shape, so that it is no longer active.

It also destabilizes the trypsin, so that it partially unfolds. This makes it an easy target for the cellular machinery that cleans up defective proteins, which destroys both the protease and the one-shot serpin.

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These two amazing crystallographic structures show before and after pictures of alpha1-antitrypsin action. PDB entry 1k9o , on the left, shows the serpin-protease complex before it is trapped. The scientists used a mutant form of the protease, with the reactive serine changed to an alanine shown in yellow , to look at the complex without tripping the trap. Second, the hyperstable polymers themselves clog up the endoplasmic reticulum of cells that synthesize serpins, eventually resulting in cell death and tissue damage. In the case of antitrypsin deficiency, antitrypsin polymers cause the death of liver cells, sometimes resulting in liver damage and cirrhosis.

Within the cell, serpin polymers are slowly removed via degradation in the endoplasmic reticulum. Physiological serpin polymers are thought to form via domain swapping events, where a segment of one serpin protein inserts into another. In the dimer of antithrombin , the RCL and part of the A-sheet incorporates into the A-sheet of another serpin molecule.

Several therapeutic approaches are in use or under investigation to treat the most common serpinopathy: antitrypsin deficiency. Serpins are the most widely distributed and largest superfamily of protease inhibitors. Most intracellular serpins belong to a single phylogenetic clade, whether they come from plants or animals, indicating that the intracellular and extracellular serpins may have diverged before the plants and animals. Protease-inhibition is thought to be the ancestral function, with non-inhibitory members the results of evolutionary neofunctionalisation of the structure.

The S to R conformational change has also been adapted by some binding serpins to regulate affinity for their targets. Many mammalian serpins have been identified that share no obvious orthology with a human serpin counterpart. Examples include numerous rodent serpins particularly some of the murine intracellular serpins as well as the uterine serpins. Uterine serpins are produced by the endometrium of a restricted group of mammals in the Laurasiatheria clade under the influence of progesterone or estrogen.

Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and three in serpin clade K with the remaining twelve classified as orphan serpins not belonging to any clade. Studies on Drosophila serpins reveal that SerpinA inhibits the Easter protease the final protease in the Nudel, Gastrulation Defective, Snake and Easter proteolytic cascade and thus controls dorsoventral patterning. As well as its central role in embryonic patterning, toll signaling is also important for the innate immune response in insects.

Accordingly, serpinA also functions to control the insect immune response.

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The genome of the nematode worm C. Further, SRP-6 inhibits lysosomal cysteine proteases released after lysosomal rupture. Accordingly, worms lacking SRP-6 are sensitive to stress. Most notably, SRP-6 knockout worms die when placed in water the hypo-osmotic stress lethal phenotype or Osl. It has therefore been suggested that lysosomes play a general and controllable role in determining cell fate.

Plant serpins were amongst the first members of the superfamily that were identified. Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases in vitro , the best-studied example being barley serpin Zx BSZx , which is able to inhibit trypsin and chymotrypsin as well as several blood coagulation factors.

The RCL of several serpins from wheat grain and rye contain poly-Q repeat sequences similar to those present in the prolamin storage proteins of the endosperm. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin CmPS-1 [] and cucumber plants. Alternative roles and protease targets for plant serpins have been proposed.

A single fungal serpin has been characterized to date: celpin from Piromyces spp. Piromyces is a genus of anaerobic fungi found in the gut of ruminants and is important for digesting plant material. Celpin is predicted to be inhibitory and contains two N-terminal dockerin domains in addition to its serpin domain. Dockerins are commonly found in proteins that localise to the fungal cellulosome , a large extracellular multiprotein complex that breaks down cellulose. Certain bacterial serpins similarly localize to the cellulosome. Predicted serpin genes are sporadically distributed in prokaryotes.

In vitro studies on some of these molecules have revealed that they are able to inhibit proteases, and it is suggested that they function as inhibitors in vivo. Several prokaryote serpins are found in extremophiles.

Summary: Serpin (serine protease inhibitor)

Accordingly, and in contrast to mammalian serpins, these molecules possess elevated resistance to heat denaturation. It is suggested that the role of cellulosome-associated serpins may be to prevent unwanted protease activity against the cellulosome. Serpins are also expressed by viruses as a way to evade the host's immune defense.

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  6. Specifically, crmA lacks the D-helix as well as significant portions of the A- and E-helices. From Wikipedia, the free encyclopedia. Superfamily of proteins with similar structures and diverse functions. A serpin white with its 'reactive centre loop' blue bound to a protease grey. Once the protease attempts catalysis it will be irreversibly inhibited. The inhibitory mechanism of serpins involves a large conformational change S to R transition.

    The serpin white first binds a protease grey with the exposed reactive centre loop blue. When this loop is cleaved by the protease, it rapidly inserts into the A-sheet light blue , deforming and inhibiting the protease.