PMID- 16973585
OWN - NLM
STAT- MEDLINE
DCOM- 20061024
LR  - 20181113
IS  - 0022-538X (Print)
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 80
IP  - 19
DP  - 2006 Oct
TI  - Structural requirements for gp80 independence of human herpesvirus 8 
      interleukin-6 (vIL-6) and evidence for gp80 stabilization of gp130 signaling 
      complexes induced by vIL-6.
PG  - 9811-21
AB  - Human herpesvirus 8 interleukin-6 (vIL-6) displays 25% amino acid identity with 
      human IL-6 (hIL-6) and shares an overall four-helix-bundle structure and 
      gp130-mediated STAT/mitogen-activated protein kinase signaling with its cellular 
      counterpart. However, vIL-6 is distinct in that it can signal through gp130 
      alone, in the absence of the nonsignaling gp80 alpha-subunit of the IL-6 
      receptor. To investigate the structural requirements for gp80 independence of 
      vIL-6, a series of expression vectors encoding vIL-6/hIL-6 chimeric and 
      site-mutated IL-6 proteins was generated. The replacement of hIL-6 residues with 
      three vIL-6-specific tryptophans implicated in gp80 independence from 
      crystallographic studies or the A and C helices containing these residues did not 
      confer gp80 independence to hIL-6. The N- and C-terminal regions of vIL-6 could 
      be substituted with hIL-6 sequences with the retention of gp80-independent 
      signaling, but substitutions of other regions of vIL-6 (helix A, A/B loop, helix 
      B, helix C, and proximal half of helix D) with equivalent sequences of hIL-6 
      abolished gp80 independence. Interestingly, the B helix of vIL-6 was absolutely 
      required for gp80 independence, despite the fact that this region contains no 
      receptor-binding residues. Point mutational analysis of helix C, which contains 
      residues involved in physical and functional interactions with gp130 domains 2 
      and 3 (cytokine-binding homology region), identified a variant, VI120EE, that was 
      able to signal and dimerize gp130 only in the presence of gp80. gp80 was also 
      found to stabilize gp130:g130 dimers induced by a distal D helix variant of vIL-6 
      that was nonetheless able to signal independently of gp80. Together, our data 
      reveal the crucial importance of overall vIL-6 structure and conformation for 
      gp80-independent signaling and provide functional and physical evidence of the 
      stabilization of vIL-6-induced gp130 signaling complexes by gp80.
FAU - Chen, Daming
AU  - Chen D
AD  - Johns Hopkins Oncology Center, 1650 Orleans Street, Room 309, Baltimore, MD 
      21231,USA.
FAU - Nicholas, John
AU  - Nicholas J
LA  - eng
GR  - R01 CA076445/CA/NCI NIH HHS/United States
GR  - CA76445/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Interleukin-6)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (interleukin-6 receptor alpha)
RN  - 133483-10-0 (Cytokine Receptor gp130)
SB  - IM
MH  - Acetylation
MH  - Amino Acid Sequence
MH  - Cell Line
MH  - Cytokine Receptor gp130/genetics/*metabolism
MH  - Dimerization
MH  - Herpesvirus 8, Human/*chemistry/genetics/*metabolism
MH  - Humans
MH  - Interleukin-6/*chemistry/genetics/*metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation/genetics
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Receptors, Interleukin-6/genetics/*metabolism
MH  - Recombinant Fusion Proteins/genetics/metabolism
MH  - Sequence Alignment
MH  - *Signal Transduction
PMC - PMC1617266
EDAT- 2006/09/16 09:00
MHDA- 2006/10/25 09:00
PMCR- 2007/02/01
CRDT- 2006/09/16 09:00
PHST- 2006/09/16 09:00 [pubmed]
PHST- 2006/10/25 09:00 [medline]
PHST- 2006/09/16 09:00 [entrez]
PHST- 2007/02/01 00:00 [pmc-release]
AID - 80/19/9811 [pii]
AID - 0872-06 [pii]
AID - 10.1128/JVI.00872-06 [doi]
PST - ppublish
SO  - J Virol. 2006 Oct;80(19):9811-21. doi: 10.1128/JVI.00872-06.