A deadly toxin with a romantic name: Panton-

Valentine Leukocidin complex

Bacterial toxins targetting host cell membranes
It may have been Valentine's day in February, but if your beloved passes on the Panton-Valentine
Leukocidin complex you might be in trouble! Leukocidins are intriguing proteins, being both soluble
and, after undergoing a substantial conformational change, integral membrane proteins.
The leukocidin family consists of staphylococcal toxins, used by pathogens to form pores in host cell
membranes to release nutrients hich the infecting bacterium can metabolise. !everal family members
have been isolated from pathogenic bacteria, mostly from staphylococci, but also from Clostridium and
Bacillus species. The first to be characteri"ed as the Panton-Valentine Leukocidin complex #PVL,
ref. $ % hich is responsible for the necrotic lesions in the skin of patients infected ith Staphylococcus
aureus. PVL is found in the ma&ority of the most dangerous antibiotic'resistant S. aureus isolates
#()!* strains ' originally from (ethicillin'resistant S. aureus, common in hospital'ac+uired
infections%.
It takes two...
,ike other leukocidins, the PVL complex is made up of to components, called #Luk-PV% and !
#Luk!-PV% that interact to make pores and induce cell lysis. -enes for both components appear to have
been originally ac+uired by the pathogens from a bacteriophage. The components, secreted by the
pathogens in soluble form, assemble to form the pore complexes at the host cell surface.
The structure of the pore in this system is as yet unknon, but the structures of Luk-PV and Luk!-
PV, in the soluble form, have been solved individually #./0 entries $pvl and $t1r, respectively%. To
form the pore, the soluble ! and components must associate and undergo a conformational change.
The mechanism of action seems to be that the ! component vie'$ binds to specific receptors on the
host cell, after hich the component vie'2 binds, leading to complex formation. (ultiple !
complexes insert into the host'cell membrane to form a pore and start cell lysis.
unctional subdomains
In spite of their relatively lo se+uence similarity #345 identical matched residues%, the and !
proteins share a common tertiary structure and can be superimposed ith a 67 atom )(!/ of less than
$.1 8. To learn about structure superimposition using the P"Be service P"Beold have a look at the
folloing tutorial9 ./0eFold mini'tutorial.
The single structural domain can be divided into three functional subdomains9 a central '#-sandwich'
hich is the heart of the soluble forms #vie'3, shon in blue%, a protruding 'rim' #vie'3, shon in
yello% and a 'stem' #vie'3, shon in red%. The stem subdomain is a small motif of to :'strands and
it is thought to be key to the pore'forming function of the toxin.
orming a pore
*nalogous to the mechanism suggested for the related toxin $-hemolysin #./0 entry ;ahl, vie'<%, it
is likely that the and ! components cooperate to penetrate the cell membrane by reorgani"ing their
stem subdomains and forming a multimeric assembly that creates a barrel'like pore. In this pore, the $-
hemolysin stem has undergone a ma&or conformational change vie'< to form a long #-hairpin. *
hairpin is a pair of hydrogen'bonded antiparallel :'strands that are connected by a tight turn. In the case
of $-hemolysin, seven of these extended hairpins combine to form a complete ring of strands creating a
barrel'like pore vie'1. The $-hemolysin structure shos ho the rim subdomains of this toxin are
positioned as a ring belo the #-sandwich subdomains here they are likely to interact ith the outer
surface of the host cell membrane. It is the pore formed by the stem subdomains that causes the cell to
lyse.
The oligomeric state of the integral membrane form of PVL complex is still unknon, but experiments
suggest a $9$ ratio of Luk-PV to Luk!-PV. This makes a heptameric pore similar to that of $-
hemolysin unlikely but a pore made up of an even number of components could achieve the same goal.
urther exploration
If you ant to explore the structures discussed here in more detail then here are some suggestions.
* good starting point is to visit the P"Be !ummary pages for each component9 ./0 entries $pvl and
$t1r. These pages collect together information and visuali"ations for each part of the PVL toxin. =ey
facts for each entry are summari"ed ith P"Bprints. This should help you +uickly spot that these to
entries appear to be from different organisms! The ! component has in fact been assigned to the
bacteriophage from hich it is presumed to be derived.
*nother +uite interesting feature of $t1r is that it has an apparently octameric assembly. /oes this have
any bearing of the structure of the pore> Try comparing the assembly in $t1r ith that in the functional
pore assembly ;ahl described above. It seems likely that in fact the %t&r octamer is an artifact deriving
from non'physiological contacts during crystalli"ation. ?ou can use the P"Be @uaternary structure
analysis service P"BePI!A to check this.
Finally, to find out ho to use the P"Beold service to compare the structures of the to PVL
components and superimpose them on $-hemolysin, you can follo the folloing P"Be'uips
tutorial9 ./0eFold mini'tutorial.
(e)erences
)ef.$ 9 ,ancet $A32 2$A 14B.
View-%
*artoon o) %t&r - the ! component o) PVL
To understand the topology #fold% of a protein, a cartoon that gradually changes colour from blue
#amino terminus% to red #carboxy terminus% can help you follo the path of the polypeptide chain
through the structure.
View-+
(ainbow colouring o) a cartoon o) %p,l - the component o) PVL
To understand the topology #fold% of a protein, a cartoon that gradually changes colour from blue
#amino terminus% to red #carboxy terminus% can help you follo the path of the polypeptide chain
through the structure.
View--
unctional subdomains in the ! component o) PVL. %tsr
The :'sandich #blue%, stem #red% and rim #yello% subdomains.
View-/
0he heptameric pore in 1ahl 2 $-hemolysin
!even protein subunits form a :'barrel pore
View-&
A single subunit in the heptameric pore o) $-hemolysin 31ahl4
Isolating a single protein subunit shos the functional subdomains that are shared ith the .V,
proteins. The stem domain #red% has extended don to form a pair of antiparallel :'strands in the
barrel'like pore.