Poxvirus Secreted Chemokine-binding Proteins

4 Pages·0.059 MB·English

by  McFadden G., Moyer R.

Poxvirus Secreted
Chemokine-binding
Proteins
Grant McFadden1,* and Richard Moyer2
1The John P. Robarts Research Institute and Department of Microbiology and Immunology,
The University of Western Ontario, 1400 Western Road, London, Ontario, N6G 2V4, Canada
2Department of Molecular Genetics and Microbiology, University of Florida College of Medicine,
PO Box 100266, Gainesville, FL 32610-0266, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14016.
SUMMARY BACKGROUND
Unliketheclassicviroceptors(virus-encodedreceptor Discovery
homologs) that bind and inhibit cytokines such as
TNF, interferons, and IL-1(cid:12), the viral proteins that In 1997, the discovery of secreted chemokine-binding
bind and modulate chemokines were discovered by proteins suggested a novel virus strategy for modu-
screening analysis for novel cytokine inhibitors lating chemokine functions during virus infection
expressed by poxviruses. Currently, two classes of (Graham et al., 1997). Subsequent studies revealed
chemokine-binding proteins have been described that these poxvirus-encoded chemokine-binding pro-
which interact with chemokines in different fashion. teins (CBPs)were specific inhibitorsoftheCC family
The first class, exemplified by the M-T1 protein of ofchemokines(Smithetal.,1997;Alcamı´ etal.,1998;
myxoma virus and the secreted 35K proteins from a Lalani et al., 1998). Members of this growing family
variety of orthopoxviruses, are 35–45 kDa secreted of poxvirus proteins, designated the T1/35 kDa
glycoproteins that bind and inhibit the ability of a familyofsecretedviroceptors,havebeenuncoveredin
broad spectrum of CC chemokines to engage their myxoma virus, Shope fibroma virus, cowpox virus,
cognate receptors. Binding occurs in a relatively rabbitpox virus, raccoonpox virus, variola virus, and
species-independent fashion. The second class is certain strains of vaccinia virus (see Figure 1). The
typified by the M-T7 protein of myxoma virus, discoveryofthepoxviruschemokine-bindingproteins
which was first describedas an inhibitorof IFN(cid:13) but has been reviewed in detail by Lalani and McFadden
has a second property of binding to a wide spectrum (1997).
of chemokines via the conserved glycosaminoglycan-
binding domains of these ligands. Both classes of
Alternative names
proteinsaffectthepathogenesisofvirusinfectionsbut
are believed to interfere with chemokine biological
Chemokine-binding proteins (CBPs), viral chemo-
functions by different mechanisms.
kine-binding proteins (vCKBPs), viral chemokine
inhibitors (vCCIs), and T1/35 kDa family.
2144 Grant McFadden and Richard Moyer
Structure Vaccinia virus Lister: 137559
Vaccinia virus Copenhagen: 335577
Variola virus Somalia 1977: 885856
The poxvirus CBPs constitute a family of secreted
Cowpox virus (orf B): 333518
glycoproteinsthatexhibitconsiderablesequencesimi-
Cowpox virus (D1L): 3096963
larity to each other. All the CBPs of this class share
conserved sets of sequence motifs, particularly a
characteristic cysteine-spacing arrangement (See
Sequence
Figure 1). However, to date no close cellular homol-
ogs have been described for this family.
Thecrystalstructureforonememberofthisfamily, See Figure 1.
namely the secreted 35 kDa protein from cowpox
(vCCI), has recently been determined and shown to
exhibit a novel (cid:12) sandwich fold that reveals a poten- Description of protein
tiallynewstrategytobindandinhibitCCchemokines
(Carfi et al., 1999).
Thefirstmemberofthisfamily(designated35 K)was
identified as the major secreted glycoprotein from
Main activities and cells infected with rabbitpox virus (Martinez-Pomares
et al., 1995) and certain vaccinia virus strains (e.g.
pathophysiological roles
Evans, Lister) but not others (e.g. Western Reserve,
WR) (Patel et al., 1990). Only later did functional
The members of the T1/35 kDa CBP family inhibit a studies reveal that members of this family could bind
broad spectrum of CC chemokines, as measured by and inhibit a broad spectrum of CC chemokines
receptor-bindinganalysis,calciumfluxmeasurements, in vitro (Graham et al., 1997; Smith et al., 1997;
and chemotaxis assays (Smith et al., 1997; Alcamı´ Alcamı´ etal.,1998;Lalanietal.,1998).Inadditionto
et al., 1998; Lalani et al., 1998). Expression of these the expression and secretion of CBPs from poxvirus-
viral proteins modulates the influx and activation of infectedcells, membersofthe T1/35 kDafamilyhave
monocytes/macrophages and other classes of reactive also been overexpressed in active form using bac-
leukocytes into sites of virus replication in infected ulovirus vectors and as Fc fusion constructs (Smith
animals (Martinez-Pomares et al., 1995; Graham et al., 1997; Alcamı´ et al., 1998).
et al., 1997).
Relevant homologies and species
GENE
differences
Accession numbers
No cellular homologs of the T1/35 kDa family have
been reported, and a comparison of the chemokine-
Myxoma virus (M-T1): U62677
inhibitory properties of members from vaccinia,
Shope fibroma virus (S-T1): M17433
rabbitpox, cowpox, and myxoma has revealed no
Rabbitpox virus (35K): U64724
obvious species-specificity against representative CC
Vaccinia virus Lister (C23L): D00612
chemokines (Smith et al., 1997; Lalani et al., 1998).
Vaccinia virus Copenhagen (C23L/B29R): M35027
Variola virus Somalia 1977 (G3R): U18341
Cowpox virus (ORF B): L08906
Affinity for ligand(s)
Cowpox virus (D1L): Y11842
The affinities for T1/35 kDa family members for a
variety of human and murine chemokines have been
PROTEIN
measured, and K values generally range in the pico-
d
molar to low nanomolar range for many of the
Accession numbers
representative CC chemokines tested (Smith et al.,
1997; Alcamı´ et al., 1998). Thus, the viral proteins
Myxoma virus: 2076755 have considerably greater affinities for CC chemo-
Shope fibroma virus: 139626 kines than these ligands have for their own cellular
Rabbitpox virus: 2076757 receptors.
Poxvirus Secreted Chemokine-binding Proteins 2145
Figure 1 Alignments of the poxvirus T1/35 kDa family of chemokine-binding proteins. Amino acids are
boxed if they are conserved in both myxoma virus and Shope fibroma virus, and at least four of the
orthopoxvirus members. Myx, myxoma virus; SFV, Shope fibroma virus; RPV, rabbitpox virus; VVlis,
vaccinia virus (Lister); VVcop, vaccinia virus (Copenhagen); VAR, variola virus; CPV, cowpox virus.
Conserved cysteines are marked with an asterix. Adapted from Graham et al. (1997).
Myx MT1 1 M K R L C V L F A C L A - - - - - - A T L A T K G I C R Q G E D V R Y M
SFV ST1 1 M R R L C I I L L V Y V Y - - - - - A T F A T K G I C K Q D E D V R Y M
RPV 35kDa 1 M K Q Y I V L A C M C L A A A A M P A S L Q Q S S S S S S S C T E E E N K H H M
VVlis35kDa 1 M K Q Y I V L A C M C L A A A A M P A S L Q Q S S S S S S S C T E E E N K H H M
VVcop35kDa 1 M H V P A S L Q Q S S S S S S S C T E E E N K H H M
VAR 35kDa 1 M K Q Y I V L A C M C L A A A A M P A S L Q Q S S - - - S L C T E E E N K H Y M
CPV 35kDa 1 M K Q I V L A C I C L A A V A I P T S L Q Q S F S S S S S C T E E E N K H H M
Myx MT1 31 G I D A V A K I T K R - - T T G S D T P C Q G L R T T I E S A Y T E D E N E D D
SFV ST1 32 G I D V V V K V T K K - - T S G S D T V C Q A L R T T F E A A H K G D G A N D S
RPV 35kDa 41 G I D V I I K V T K Q D Q T P T N D K I C Q S V T E I T E S E S D P D P - - - -
VVlis35kDa 41 G I D V I I K V T K Q D Q T P T N D K I C Q S V T E I T E S E S D P D P - - - -
VVcop35kDa 27 G I D V I I K V T K Q D Q T P T N D K I C Q S V T E I T E S E S D P D P - - - -
VAR 35kDa 38 G I D V I I K V T K Q D Q T P T N D K I C Q S V T E I T E S E S D P - - - - - -
CPV 35kDa 40 G I D V I I K V T K Q D Q T P T N D K I C Q S V T E V T E S E D E S E - - - - -
Myx MT1 69 G A T G T E Q P D D L S E E Y E Y D E N D E S F L T G F V I G S T Y H T I V G G
SFV ST1 70 - - L S T E Y V D D Y S E E E E Y - E Y D E S F L E G F V I G S T Y Y T I V G G
RPV 35kDa 77 - - - E V E S E D D S T S V E D V - - - - - - - - - - - D P P T T Y Y S I I G G
VVlis35kDa 77 - - - E V E S E D D S T S V E D V - - - - - - - - - - - D P P T T Y Y S I I G G
VVcop35kDa 63 - - - E V E S E D D S T S V E D V - - - - - - - - - - - D P P T T Y Y S I I G G
VAR 35kDa 72 - - - E V E S E D D S T S V E D V - - - - - - - - - - - D P P T T Y Y S I I G G
CPV 35kDa 75 - - - E V V K G D - - - - - - - - - - - - - - - - - - - - - P T T Y Y T V V G G
Myx MT1 109 G L S V T F G F T G C P T V K A I S E H V K G R H V Y V R L S S D A P W R D T N
SFV ST1 107 G L S V T F G F T G C P T V K S V S E Y A K G R I V F I R L S S D A P W R D T N
RPV 35kDa 103 G L R M N F G F T K C P Q I K S I S E S A D G N T V N A R L S S V S P G Q G K D
VVlis35kDa 103 G L R M N F G F T K C P Q I K S I S E S A D G N T V N A R L S S V S P G Q G K D
VVcop35kDa 89 G L R M N F G F T K C P Q I K S I S E S A D G N T V N A R L S S V S P G Q G K D
VAR 35kDa 98 G L R M N F G F T K C P Q I K S I S E S A N G N A V N A R L S S V P P G Q G K D
CPV 35kDa 91 G L T M D F G F T K C P K I S S I S E Y S D G N T V N A R L S S V S P G Q G K D
Myx MT1 149 P V S M N R T E A L A L L D T C E V S V D I K C S R V N V T E T T Y G T A A L V
SFV ST1 147 P M S I N R T E A L A L L E K C E T S I D I K C S N E T V S E T T Y G L A S L A
RPV 35kDa 143 S P A I T H E E A L A M I K D C E V S I D I R C S E E E K D S D I K T H P V L G
VVlis35kDa 143 S P A I T R E E A L A M I K D C E V S I D I R C S E E E K D S D I K T H P V L G
VVcop35kDa 129 S P A I T R E E A L A M I K D C E V S I D I R C S E E E K D S D I K T H P V L G
VAR 35kDa 138 S P A I T R V E A L A M I K D C E L S I D I R C S E E E K D S D I Q T H P V L E
CPV 35kDa 131 S P A I T R E E A L S M I K D C E M S I N I K C S E E E K D S N I K T H P V L G
Myx MT1 189 P R I T Q A T R - R S H I I G S T L V D T E C V K S L D I T V Q V G E M C K R T
SFV ST1 187 P H I T Q A T E - R G N I I G S T L V D T D C V E N L D V T V H L G E M C R K T
RPV 35kDa 183 S N I S H K K V S Y E D I I G S T I V D T K C V K N L E F S V R I G D M C K E S
VVlis35kDa 183 S N I S H K K V S Y E D I I G S T I V D T K C V K N L E F S V R I G D M C K E S
VVcop35kDa 169 S N I S H K K V S Y E D I I G S T I V D T K C V K N L E F S V R I G D M C K E S
VAR 35kDa 178 S N I S H K K V S Y E D I I G S T I V D T K C V K N L E F S V R I G D M C K E S
CPV 35kDa 171 S N I S H K K V S Y E D I I G S T I V D T K C V K N L E I S V R I G D M C K E S
Myx MT1 228 S D L S A R D S L K V K N G - - - K L L E D D I L V L R T P T L K A C N 260
SFV ST1 226 S D L S K R D S L K V K N G - - - E L L D D D T F S I H T P K L K A C N 258
RPV 35kDa 223 S E L E V K D G F K Y V D G S A S K G A T D D T S L I D S T K L K A C V 258
VVlis35kDa 223 S E L E V K D G F K Y V D G S A S E G A T D D T S L I D S T K L K A C V 258
VVcop35kDa 209 S E L E V K D G F K Y V D G S A S E G A T D D T S L I D S T K L K A C V 244
VAR 35kDa 218 S D L E V K D G F K Y V D G S V S E G V T D D T S L I D S T K L K S C V 253
CPV 35kDa 211 S E L E V K D G F K Y V D G S A S E D A A D D T S L I N S A K L I A C V 246
2146 Grant McFadden and Richard Moyer
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