Nerve tissue protein

Neurodegenerative disease is caused by prions accumulation of PrPsc. The brains of humans or animals affected with prion disease show characteristics histopathological changes. However, the pathogenesis of the disease is largely unknown and treatment is often unsatisfactory. Tests on 60-week-old mice investigated PrPc – deficient mice showed chronic demyelinating polyneuropathy. Chronic demyelinating polyneuropathy was 100% penetrant and conspicuous in all investigated peripheral nerves. Large fibers we affected in axons when morphometry was used and identical pathologies were detected in the sciatic nerves.[3]

Neuronal apoptosis inhibitory protein (NAIP) belongs to the family of proteins called the inhibiter of apoptosis family (IAP), these proteins are one of the key regulators of apoptosis. However, when NAIP use baculovirus IAP-repeat (BIR) domains to interact with caspases, they inhibit otherwise automatic formation of procaspase-9, an apoptosis initiator.[4]

The three-dimensional structure of all BIR domains is constructed of two to three NH2-terminus α-helices, a central antiparallel β-sheet, and two to three carboxy-terminus α-¬helices. IAP-binding motifs (IBMs) are constructed from amino-terminal tetrapeptides. The binding sites of the IBMs are between the last strand of the β-sheet and the nearby α-¬helix. The zinc ion is chelated by one histidine and three cysteines. The NH2-terminus serine binds to IBM-binding groove, P1’. The serine chain (S) is inserted into an amino acid hydrophobic pocket. Once in this pocket, hydrogen bonds attach to the oxygen atom of the serine chain, also the oxygen atom at P1’ forms another hydrogen bond to the tryptophan chain. The tryptophan chain also interacts with the carbon atoms of the arginine at P3’. A backbone of nitrogen and oxygen at P2’ and of nitrogen at P4’ provide stability.[5]

When coexpressed, the presence of both NAIP and hippocalcin caused neuroblastoma cells to be protected from cell death through the induction of increased calcium levels.[5]

NAIP has been shown to be involved in the inherited disease spinal muscular atrophy. The interaction between NAIP and hippocalcin, a neuronal calcium-sensor protein, has been observed to take place in the zinc-binding region along with other specific amino acids. In sympathetic neurons, the expression of NAIP-BIR3 and hippocalcin did not provide any significant protection from cell death from the withdrawal of nerve growth factor. This is unexpected because, in nerve growth factor withdrawal, caspase-3 and -9 are activated, causing cell death, which are the very caspases blocked by NAIP.[4]

Hippocalcin is a neuronal calcium-sensor protein which has two to three regions that can bind with calcium ions.[5]

The X-linked IAP (XIAP) is an extremely powerful inhibitor of apoptosis. This is done through the binding to caspases directly. Similar to the functionality of NAIP, the BIR3 domain of XIAP binds to the carboxyl-terminal subunit of caspase-9. Between S1 and S1’ is where the catalysis occurs. In caspase-3 the ‘hook’ and ‘sinker’ attach. Both the BIR2 and BIR3 have a groove that is predominately negatively charged. This negative charge in BIR3 allows the attachment of the IAP-binding motif, causing enzymatic activity to be inhibited.[6]
When overexpressed, XIAP is able to block caspases extremely well and prevents cell death of sympathetic neurons when nerve growth factors are deprived.[7]