PMID- 10212286
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 18
DP  - 1999 Apr 30
TI  - Bidirectional transmembrane modulation of integrin alphaIIbbeta3 conformations.
PG  - 12945-9
AB  - Activation of blood platelets by physiological stimuli (e.g. thrombin, ADP) at
      sites of vascular injury induces inside-out signaling, resulting in a
      conformational change of the prototype integrin alphaIIbbeta3 from an inactive to
      an active state competent to bind soluble fibrinogen. Furthermore, ligand
      occupancy of alphaIIbbeta3 initiates outside-in signaling and additional
      conformational changes of the receptor, leading to the exposure of extracellular 
      neoepitopes termed ligand-induced binding sites (LIBS), which are recognized by
      anti-LIBS monoclonal antibodies. To date, the mechanism of bidirectional
      transmembrane signaling of alphaIIbbeta3 has not been established. In this study,
      using our newly developed anti-LIBScyt1 monoclonal antibody, we showed that
      extracellular ligand binding to alphaIIbbeta3 on blood platelets induces a
      transmembrane conformational change in alphaIIbbeta3, thereby exposing the
      LIBScyt1 epitope in the alphaIIb cytoplasmic sequence between Lys994 and Asp1003.
      In addition, a point mutation at this site (P998A/P999A) renders alphaIIbbeta3
      constitutively active to bind extracellular ligands, resulting in
      fibrinogen-dependent cell-cell aggregation. Taken collectively, these results
      demonstrated that the extracellular ligand-binding site and a cytoplasmic LIBS
      epitope in integrin alphaIIbbeta3 are conformationally and functionally coupled. 
      Such bidirectional modulation of alphaIIbbeta3 conformation across the cell
      membrane may play a key role in inside-out and outside-in signaling via this
      integrin.
FAU - Leisner, T M
AU  - Leisner TM
AD  - Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, USA.
FAU - Wencel-Drake, J D
AU  - Wencel-Drake JD
FAU - Wang, W
AU  - Wang W
FAU - Lam, S C
AU  - Lam SC
LA  - eng
GR  - HL-41793/HL/NHLBI NIH HHS/United States
GR  - HL-52755/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA Primers)
RN  - 0 (Epitopes)
RN  - 0 (Ligands)
RN  - 0 (Platelet Glycoprotein GPIIb-IIIa Complex)
SB  - IM
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Binding Sites
MH  - DNA Primers
MH  - Epitopes/metabolism
MH  - Fluorescent Antibody Technique, Indirect
MH  - Humans
MH  - Ligands
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Platelet Glycoprotein GPIIb-IIIa Complex/chemistry/genetics/*metabolism
MH  - Protein Conformation
EDAT- 1999/04/23 00:00
MHDA- 1999/04/23 00:01
CRDT- 1999/04/23 00:00
PHST- 1999/04/23 00:00 [pubmed]
PHST- 1999/04/23 00:01 [medline]
PHST- 1999/04/23 00:00 [entrez]
AID - 10.1074/jbc.274.18.12945 [doi]
AID - S0021-9258(19)73441-3 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 30;274(18):12945-9. doi: 10.1074/jbc.274.18.12945.