Caspase

Caspases ( cysteinyl - aspartate specific protease English ) are a group of cysteine ​​proteases, the caspases other intersect at a peptide bond C - terminal aspartate, where the name comes from. Caspases are in animals, the most important enzymes of apoptosis, the programmed cell death.

Properties

Caspases are essential for the correct development of an organism, but also for the response of a cell to severe damage (e.g., by radiation ), or infection by intracellular pathogens, such as viruses.

The caspases are part of an enzyme cascade in the initiation of apoptosis. For triggering of cell death first initiator caspases (eg, caspase -8 and 9) enabled. This in turn cleave the pro- form ( precursor form ) downstream caspases ( effector caspases, including caspase 3, 7, 6), the cell's own proteins such as actin and Lamin among other columns. Another important function of the effector caspase activation is a nuclease that cleaves within the nuclear DNA of apoptosis between the histones, which are in an agarose gel showing a DNA ladder.

Caspases are in addition to the apoptosis in the development of red blood cells, and myoblasts, and involved in synaptic plasticity.

Defects in caspases are involved in the development of tumors. Some viruses and intracellular living bacteria try to suppress a caspase activation in the course of immune evasion. Some viruses use to activate caspases their own proteins. Other diseases with disorders of caspase cascade are eg protein misfolding diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, as well as stroke, ischemia, congestive heart failure, systemic lupus erythematosus, autoimmune lymphoproliferative syndrome, rheumatoid arthritis and thyroiditis.

Types

In humans, twelve different caspases have been described previously. These are divided into three groups: Pro-inflammatory caspases, initiator caspases and effector caspases. Initiator caspases (eg CASP2, CASP8, CASP9 and CASP10 ) cut effector caspases into their active form. Effector caspases (eg, CASP3, CASP6, CASP7 ), however, cut other cellular proteins of apoptosis. The activation is inhibited by caspase inhibitors.

CASP1, CASP4 and CASP5 are inflammatory caspases and involved in the maturation of T - cells. CASP4 CASP5 and are overexpressed in many forms of vitiligo and related NALP1 -associated autoimmune disorders.

Caspase cascade

The activity of caspases is not activated by modification of gene expression, but by posttranslational modification via proteolysis. Initiator caspases cut more caspases in their active form, resulting in an exponential signal amplification. Due to the proteolytic activation of caspases other proteins are broken down in a row increasing. Thus, the apoptosis initiated faster. At the initiator caspases separated prodomains are longer than effector caspases. The prodomain of initiator caspases contain a CARD domain (such as Caspase-2 and -9 ), or death effector domain ( DED), ( in caspase-8 and -10 ). Upon activation of the initiator caspases are grouped together and activate additionally by mutual proteolysis.

Initiator caspases are activated by different enzymes:

• Granzyme B is secreted by cytotoxic T cells and NK cells, resulting in caspase -3 and -7 is activated.
• Death receptors such as Fas receptors, TRAIL receptors, TNF receptors which activate caspase -8 and -10.
• The apoptosome ( regulated by cytochrome c and Bcl -2 family ), the activated caspase- 9th

The effector caspases cut various cellular proteins:

• Lamine
• ICAD/DFF45 ( inhibitor of caspase -activated DNase or DNA fragmentation factor 45)
• PARP (Poly- ADP-ribose polymerase)
• PAK2 (P - 21 activated kinase 2)

Protein ICAD/DFF45 inhibits caspase -activated DNase (CAD). Proteolysis by effector caspases inactivated this inhibition, thereby, the DNA is fragmented in the cell. The caspase -1 and -3 in macrophages are inhibited by the DNA-binding proteins HIN -200 (synonym p202 ) or by AIM2 ' (synonym p210 ) enabled.

History

H. Robert Horvitz discovered the involvement of the gene ced- 3 (from Caenorhabditis elegans death gene) in programmed cell death. Horvitz and his colleague Junying Yuan in 1993 discovered the similarity of CED- 3 to the mammalian cysteine ​​protease interleukin- 1 beta converting enzyme (ICE, now known as caspase -1). The nomenclature of caspases was adopted in 1996, as a result of the simultaneous detection in a plurality of groups of researchers often have different names have been used, such as caspase-3 as CPP32, Yama, apopain, and was described. The caspases have been renamed in the order of their discovery.