Defining the interaction of perforin with calcium and the phospholipid membrane.
Following its secretion from cytotoxic lymphocytes into the immune synapse, perforin binds to target cell membranes through its Ca(2+)-dependent C2 domain. Membrane-bound perforin then forms pores that allow passage of pro-apoptopic granzymes into the target cell. In the present study, structural and biochemical studies reveal that Ca(2+) binding triggers a conformational change in the C2 domain that permits four key hydrophobic residues to interact with the plasma membrane. However, in contrast with previous suggestions, these movements and membrane binding do not trigger irreversible conformational changes in the pore-forming MACPF (membrane attack complex/perforin-like) domain, indicating that subsequent monomer-monomer interactions at the membrane surface are required for perforin pore formation.
††Crystallography, Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, U.K.
Daouda A K
DA
Traore
Amelia J
AJ
Brennan
Ruby H P
RH
Law
Con
C
Dogovski
Matthew A
MA
Perugini
Natalya
N
Lukoyanova
Eleanor W W
EW
Leung
Raymond S
RS
Norton
Jamie A
JA
Lopez
Kylie A
KA
Browne
Hideo
H
Yagita
Gordon J
GJ
Lloyd
Annette
A
Ciccone
Sandra
S
Verschoor
Joseph A
JA
Trapani
James C
JC
Whisstock
Ilia
I
Voskoboinik
D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats
D010743:Phospholipids; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; C510465:perforin, rat; D002118:Calcium