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PDBsum entry 4qxw
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Cell adhesion
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PDB id
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4qxw
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PDB id:
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| Name: |
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Cell adhesion
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Title:
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Crystal structure of the human ceacam1 membrane distal amino terminal (n)-domain
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Structure:
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Carcinoembryonic antigen-related cell adhesion molecule 1. Chain: a, b. Fragment: n terminal domain. Synonym: biliary glycoprotein 1, bgp-1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ceacam1, bgp, bgp1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.04Å
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R-factor:
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0.206
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R-free:
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0.242
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Authors:
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Y.H.Huang,A.K.Gandhi,A.Russell,Y.Kondo,Q.Chen,G.A.Petsko,R.S.Blumberg
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Key ref:
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Y.H.Huang
et al.
(2015).
CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
Nature,
517,
386-390.
PubMed id:
DOI:
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Date:
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22-Jul-14
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Release date:
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12-Nov-14
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PROCHECK
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Headers
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References
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P13688
(CEAM1_HUMAN) -
Carcinoembryonic antigen-related cell adhesion molecule 1 from Homo sapiens
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Seq:
Struc:
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526 a.a.
107 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Nature
517:386-390
(2015)
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PubMed id:
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CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
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Y.H.Huang,
C.Zhu,
Y.Kondo,
A.C.Anderson,
A.Gandhi,
A.Russell,
S.K.Dougan,
B.S.Petersen,
E.Melum,
T.Pertel,
K.L.Clayton,
M.Raab,
Q.Chen,
N.Beauchemin,
P.J.Yazaki,
M.Pyzik,
M.A.Ostrowski,
J.N.Glickman,
C.E.Rudd,
H.L.Ploegh,
A.Franke,
G.A.Petsko,
V.K.Kuchroo,
R.S.Blumberg.
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ABSTRACT
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T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is
an activation-induced inhibitory molecule involved in tolerance and shown to
induce T-cell exhaustion in chronic viral infection and cancers. Under some
conditions, TIM-3 expression has also been shown to be stimulatory. Considering
that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death
1 (PD-1), is being targeted for cancer immunotherapy, it is important to
identify the circumstances under which TIM-3 can inhibit and activate T-cell
responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with
carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known
molecule expressed on activated T cells and involved in T-cell inhibition.
Biochemical, biophysical and X-ray crystallography studies show that the
membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each
is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with
inhibitory function. CEACAM1 facilitates the maturation and cell surface
expression of TIM-3 by forming a heterodimeric interaction in cis through the
highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and
TIM-3 also bind in trans through their N-terminal domains. Both cis and trans
interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function
of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells
are hyper-inflammatory with reduced cell surface expression of TIM-3 and
regulatory cytokines, and this is restored by T-cell-specific CEACAM1
expression. During chronic viral infection and in a tumour environment, CEACAM1
and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to
enhancement of anti-tumour immune responses with improved elimination of tumours
in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand
for TIM-3 that is required for its ability to mediate T-cell inhibition, and
this interaction has a crucial role in regulating autoimmunity and anti-tumour
immunity.
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Links
