Early 35 kDa protein

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Early 35 kDa protein (AcMNPV)
UniProt
P08160
Other data
Chromosome0: 0.12 - 0.12 Mb
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StructuresSwiss-model
DomainsInterPro
Early 35 kDa protein (BmNPV)
Identifiers
OrganismBombyx mori nuclear polyhedrosis virus (BmNPV)
SymbolP35
UniProt
P31354
Other data
Chromosome0: 0.11 - 0.11 Mb
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StructuresSwiss-model
DomainsInterPro

The Early 35 kDa protein, or P35 in short, is a

baculoviral protein that inhibits apoptosis in the cells infected by the virus. Although baculoviruses infect only invertebrates in nature, ectopic expression of P35 in vertebrate animals and cells also results in inhibition of apoptosis, thus indicating a universal mechanism. P35 has been shown to be a caspase
inhibitor with a very wide spectrum of activity both in regard to inhibited caspase types and to species in which the mechanism is conserved.

Species distribution

P35 has been found in different strains of the

nuclear polyhedrosis virus, a species of baculovirus that infects insects. Two orthologs of P35 that have been studied in detail are the ones from the Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV) and from the Bombyx mori nuclear polyhedrosis virus (BmNPV). The P35 ortholog from AcMNPV was found to block apoptosis in mammalian cells much more efficiently as compared to the ortholog from BmNPV.[2]

Function

The P35 protein inhibits apoptosis by acting as a

caspases.[3] P35 first serves as a caspase substrate and is cleaved between the amino acids D87 and G88, i.e. after the sequence DQMD in P35 from AcMNPV and after the sequence DKID in P35 from BmNPV, resulting in two polypeptide products of about 10 kDa and 25 kDa in size.[3] The cleavage site is situated in a solvent-exposed loop that extends from the protein's beta sheet core, thus ensuring good accessibility to the caspase.[1][4] However, unlike other caspase substrate proteins, the fragments of P35 do not dissociate from the caspase after cleavage. Instead, the N-terminal, 10 kDa cleavage fragment remains bound to the caspase by a covalent, stable thioester bond between the cleavage residue D87 of P35 and the cysteine residue at the active site of the caspase.[5]

While the formation of a thioester intermediate between the aspartate of the substrate's recognition site and the cysteine of the caspase's active site is a normal event in caspase-mediated protein cleavage, the resulting bond is normally quickly hydrolysed so that the cleaved products can detach. In the case of P35, however, the caspase-substrate complex remains stable. Cleavage of P35 triggers rapid conformational changes that reposition its N-terminus, which is normally buried in the protein's beta-sheet core, to the caspase's active site. As a consequence of this rearrangement, the N-terminal P35 residues C2 and V3 interact with the caspase's active site to displace water and prevent the hydrolysis reaction. The P35 residue C2 competes with the caspase's active site cysteine residue for binding of the P35 residue D87, keeping the reaction trapped in an equilibrium state.[5][6][7][8]

Interactions

In insect cells, P35 inhibits an enzyme called

CASP10.[10]

Clinical significance

Since baculoviridae infect only insects and not humans, the function of P35 in the immune evasion of infected cells is not clinically relevant. However, P35 has been considered as a potential tool in

immune rejection or in the killing of bystander cells in cancer therapy; such methods are still far from clinical application though.[11]

History and discovery

The role of P35 in the inhibition of apoptosis was first described by Rollie J. Clem in the research group of

Weill Cornell Medical College in 2001.[5]

References

  1. ^
    PMID 10205157
    .
  2. S2CID 29840073
    .
  3. ^
    PMID 8709252
    .
  4. PMID 10473544
    .
  5. ^
    S2CID 279649
    .
  6. PMID 11683637
    .
  7. PMID 12458208
    .
  8. PMID 16492559
    .
  9. PMID 8999805
    .
  10. PMID 9692966
    .
  11. PMID 20836875
    .
  12. PMID 1962198
    .
  13. PMID 7569933
    .
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