PMID- 10395669
OWN - NLM
STAT- MEDLINE
DCOM- 19990729
LR  - 20191210
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 163
IP  - 2
DP  - 1999 Jul 15
TI  - Determination of residues involved in ligand binding and signal transmission in
      the human IFN-alpha receptor 2.
PG  - 766-73
AB  - The human IFN-alpha receptor (hIFNAR) is a complex composed of at least two
      chains, hIFNAR1 and hIFNAR2. We have performed a structure-function analysis of
      hIFNAR2 extracellular domain regions using anti-hIFNAR2 mAbs (1D3, 1F3, and 3B7) 
      and several type I human IFNs. These mAbs block receptor activation, as
      determined by IFN-stimulated gene factor 3 formation, and block the antiviral
      cytopathic effects induced by type I IFNs. We generated alanine substitution
      mutants of hIFNAR2-IgG and determined that regions of hIFNAR2 are important for
      the binding of these blocking mAbs and hIFN-alpha2/alpha1. We further
      demonstrated that residues E78, W101, I104, and D105 are crucial for the binding 
      of hIFN-alpha2/alpha1 and form a defined protrusion when these residues are
      mapped upon a structural model of hIFNAR2. To confirm that residues important for
      ligand binding are indeed important for IFN signal transduction, we determined
      the ability of mouse L929 cells expressing hIFNAR2 extracellular domain mutants
      to mediate hIFN signal. hIFN-alpha8, previously shown to signal a response in
      L929 cells expressing hIFNAR1, was unable to signal in L929 cells expressing
      hIFNAR2. Transfected cells expressing hIFNAR2 containing mutations at residues
      E78, W101, I104, or D105 were unresponsive to hIFN-alpha2, but remained
      responsive to hIFN-beta. In summary, we have identified specific residues of
      hIFNAR2 important for the binding to hIFN-alpha2/1 and demonstrate that specific 
      regions of the IFNAR interact with the subspecies of type I IFN in different
      manners.
FAU - Chuntharapai, A
AU  - Chuntharapai A
AD  - Department of Antibody Technology, Genentech Inc., South San Francisco, CA 94080,
      USA.
FAU - Gibbs, V
AU  - Gibbs V
FAU - Lu, J
AU  - Lu J
FAU - Ow, A
AU  - Ow A
FAU - Marsters, S
AU  - Marsters S
FAU - Ashkenazi, A
AU  - Ashkenazi A
FAU - De Vos, A
AU  - De Vos A
FAU - Jin Kim, K
AU  - Jin Kim K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Amino Acids)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (IFNAR1 protein, human)
RN  - 0 (Interferon Type I)
RN  - 0 (Ligands)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Interferon)
RN  - 156986-95-7 (Receptor, Interferon alpha-beta)
SB  - AIM
SB  - IM
MH  - Amino Acid Substitution/genetics
MH  - Amino Acids/genetics/immunology/*metabolism
MH  - Animals
MH  - Antibodies, Monoclonal/chemistry/pharmacology
MH  - Binding Sites, Antibody/genetics
MH  - Binding, Competitive/genetics/immunology
MH  - Cell Line
MH  - HeLa Cells
MH  - Humans
MH  - Interferon Type I/*metabolism
MH  - L Cells
MH  - Ligands
MH  - Membrane Proteins
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Models, Molecular
MH  - Protein Binding/genetics/immunology
MH  - Receptor, Interferon alpha-beta
MH  - Receptors, Interferon/immunology/*metabolism/physiology
MH  - Signal Transduction/genetics/*immunology
MH  - Transfection
EDAT- 1999/07/08 00:00
MHDA- 1999/07/08 00:01
CRDT- 1999/07/08 00:00
PHST- 1999/07/08 00:00 [pubmed]
PHST- 1999/07/08 00:01 [medline]
PHST- 1999/07/08 00:00 [entrez]
AID - ji_v163n2p766 [pii]
PST - ppublish
SO  - J Immunol. 1999 Jul 15;163(2):766-73.