PMID- 29180446
OWN - NLM
STAT- MEDLINE
DCOM- 20181126
LR  - 20221109
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 2
DP  - 2018 Jan 12
TI  - Quantitative ligand and receptor binding studies reveal the mechanism of 
      interleukin-36 (IL-36) pathway activation.
PG  - 403-411
LID - 10.1074/jbc.M117.805739 [doi]
AB  - IL-36 cytokines signal through the IL-36 receptor (IL-36R) and a shared subunit, 
      IL-1RAcP (IL-1 receptor accessory protein). The activation mechanism for the 
      IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist 
      (IL-36alpha, IL-36beta, or IL-36gamma) forms a binary complex with IL-36R, which then 
      recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP 
      even in the absence of an agonist. To elucidate the IL-36 activation mechanism, 
      we considered all possible binding events for IL-36 ligands/receptors and 
      examined these events in direct binding assays. Our results indicated that the 
      agonists bind the IL-36R extracellular domain with micromolar affinity but do not 
      detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that 
      IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of 
      IL-36alpha, however, IL-1RAcP bound IL-36R strongly. These results suggested that the 
      main pathway to the IL-36R.IL-36alpha.IL-1RAcP ternary complex is through the 
      IL-36R.IL-36alpha binary complex, which recruits IL-1RAcP. We could not measure the 
      binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment 
      crystallizable-linked construct to induce IL-36R.IL-1RAcP heterodimerization and 
      predicted the binding affinity during a complete thermodynamic cycle to be 74 mum 
      The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R 
      with higher affinity and a much slower off rate than the IL-36R agonists, 
      shedding light on IL-36 pathway inhibition. Our results reveal the landscape of 
      IL-36 ligand and receptor interactions, improving our understanding of IL-36 
      pathway activation and inhibition.
CI  - (c) 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Zhou, Li
AU  - Zhou L
AD  - From the AbbVie Bioresearch Center, Worcester, Illinois 01605 and 
      li.zhou@abbvie.com.
FAU - Todorovic, Viktor
AU  - Todorovic V
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - Kakavas, Steve
AU  - Kakavas S
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - Sielaff, Bernhard
AU  - Sielaff B
AD  - From the AbbVie Bioresearch Center, Worcester, Illinois 01605 and.
FAU - Medina, Limary
AU  - Medina L
AD  - From the AbbVie Bioresearch Center, Worcester, Illinois 01605 and.
FAU - Wang, Leyu
AU  - Wang L
AD  - From the AbbVie Bioresearch Center, Worcester, Illinois 01605 and.
FAU - Sadhukhan, Ramkrishna
AU  - Sadhukhan R
AD  - From the AbbVie Bioresearch Center, Worcester, Illinois 01605 and.
FAU - Stockmann, Henning
AU  - Stockmann H
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - Richardson, Paul L
AU  - Richardson PL
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - DiGiammarino, Enrico
AU  - DiGiammarino E
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - Sun, Chaohong
AU  - Sun C
AD  - AbbVie Inc., North Chicago, Illniois 60064.
FAU - Scott, Victoria
AU  - Scott V
AD  - AbbVie Inc., North Chicago, Illniois 60064.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171127
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Chemokine CXCL1)
RN  - 0 (IL36G protein, human)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukin-1 Receptor Accessory Protein)
RN  - 0 (Receptors, Interleukin)
RN  - 0 (interleukin-36 receptor, human)
SB  - IM
MH  - Cell Line, Tumor
MH  - Chemokine CXCL1/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Interleukin-1/*metabolism
MH  - Interleukin-1 Receptor Accessory Protein/metabolism
MH  - Kinetics
MH  - Protein Binding
MH  - Receptors, Interleukin/*metabolism
MH  - Surface Plasmon Resonance
PMC - PMC5767850
OTO - NOTNLM
OT  - IL-1Rrp2
OT  - IL-36R
OT  - immunology
OT  - kinetics
OT  - protein-protein interaction
OT  - signaling
OT  - surface plasmon resonance (SPR)
COIS- All authors are employees of AbbVie. The design, study conduct, and financial 
      support for this research were provided by AbbVie. AbbVie participated in the 
      interpretation of data, review, and approval of the publication
EDAT- 2017/11/29 06:00
MHDA- 2018/11/27 06:00
PMCR- 2019/01/12
CRDT- 2017/11/29 06:00
PHST- 2017/07/06 00:00 [received]
PHST- 2017/11/15 00:00 [revised]
PHST- 2017/11/29 06:00 [pubmed]
PHST- 2018/11/27 06:00 [medline]
PHST- 2017/11/29 06:00 [entrez]
PHST- 2019/01/12 00:00 [pmc-release]
AID - S0021-9258(20)40426-0 [pii]
AID - M117.805739 [pii]
AID - 10.1074/jbc.M117.805739 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Jan 12;293(2):403-411. doi: 10.1074/jbc.M117.805739. Epub 2017 
      Nov 27.