2001
DOI: 10.1074/jbc.m103930200
|View full text |Cite
|
Sign up to set email alerts
|

Crystal Structure of Baculovirus P35 Reveals a Novel Conformational Change in the Reactive Site Loop after Caspase Cleavage

Abstract: Baculovirus P35 is a universal suppressor of apoptosis that stoichiometrically inhibits cellular caspases in a novel cleavage-dependent mechanism. Upon caspase cleavage at Asp-87, the 10-and 25-kDa cleavage products of P35 remain tightly associated with the inhibited caspase. Mutations in the ␣-helix of the reactive site loop preceding the cleavage site abrogate caspase inhibition and antiapoptotic activity. Substitution of Pro for Val-71, which is located in the middle of this ␣-helix, produces a protein that… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
1
1
1
1

Citation Types

1
16
0

Year Published

2003
2003
2011
2011

Publication Types

Select...
5
4

Relationship

1
8

Authors

Journals

citations
Cited by 31 publications
(17 citation statements)
references
References 27 publications
1
16
0
Order By: Relevance
“…Consistent with this prediction, mutations that weaken the association between the RSL and the p35 bow (Y82A and ⌬252-258), mutations that weaken the integrity of the base helix (V71P and I67K) (21,31), and an insertion mutation that lengthens the string (insertion of AlaSer after residue 83) (29), all abolish caspase inhibition by p35. This tension model is further supported by the structural similarity between the cleaved structure of an inhibition-defective p35 mutant V71P and the cleaved structure of wild-type p35 as in complex with caspase-8 (22,32). This similarity suggests that the V71P mutant does not have a gross structural defect but exhibits a tension defect due to a weaker base helix.…”
Section: Fig 3 Bowstring Kinetic Model Of Caspase Inhibition By P35supporting
confidence: 51%
“…Consistent with this prediction, mutations that weaken the association between the RSL and the p35 bow (Y82A and ⌬252-258), mutations that weaken the integrity of the base helix (V71P and I67K) (21,31), and an insertion mutation that lengthens the string (insertion of AlaSer after residue 83) (29), all abolish caspase inhibition by p35. This tension model is further supported by the structural similarity between the cleaved structure of an inhibition-defective p35 mutant V71P and the cleaved structure of wild-type p35 as in complex with caspase-8 (22,32). This similarity suggests that the V71P mutant does not have a gross structural defect but exhibits a tension defect due to a weaker base helix.…”
Section: Fig 3 Bowstring Kinetic Model Of Caspase Inhibition By P35supporting
confidence: 51%
“…A predicted viral protein, CUN75, has marginal similarity to AcMNPV P35, but lacks a conserved reactive site loop that is required for caspase-inhibition activity. 37 We did not find any antiapoptotic effect of cun75 when co-transfected with mx_Cu.qu or mx_Ae.ae. As the only dipteran baculovirus with genomic information, CuniNPV is distantly related to lepidopteran baculoviruses and lacks identifiable orthologs to many important genes such as the ie genes.…”
Section: Discussionmentioning
confidence: 89%
“…In the structure of human caspase-3 complexed with isatin sulfonamide inhibitor, the N terminus extends down where it interacts with a symmetry related molecule (47). In the caspase-3 structures complexed with tetrapeptide inhibitor (16,17), the first residue observed is Asn 35 , which corresponds to Pro 51 of Sf-caspase-1. The first residue of the human caspase-7 and -8 structures also corresponds to Pro 51 of Sfcaspase-1.…”
Section: Resultsmentioning
confidence: 99%
“…Sf-caspase-1 is the principal effector caspase of Spodoptera frugiperda, a nocturnal moth infected by the large DNA baculoviruses. This invertebrate caspase is of interest because it is the main target of the baculovirus apoptosis suppressor P35 (13,26), a pancaspase inhibitor with a novel mechanism of stoichiometric inhibition (32)(33)(34)(35). Sf-caspase-1 displays 41 and 39% protein sequence identity to human effector caspases-7 and -3, respectively (26).…”
mentioning
confidence: 99%