Research Interests:
Recognition and Signaling by Immunoreceptors
We aim at resolving, in molecular and quantitative terms the mechanisms of
recognition performed by the multichain immunorecognition receptors (MIRRs) and
the mechanisms which couple them to the respective cellular response. We perform
direct measurements, by fluorescence methods, of peptide binding in homogeneous
solutions to recombinant human and mouse class I molecules. These yield detailed
thermodynamic and kinetic insights into the mutual interactions among the components
of these ternary complexes: Assembly of mouse H2-Kd and H2-Kb as well as human A-2
ternary complexes with a range of specific peptides was shown to exhibit allosteric
control; while peptide binding to the heterodimer enhances
-2m binding to
the heavy chain; peptide's affinity to the heavy chain drastically increases upon
-2m binding. These ternary complexes of class I MHC molecules with peptides
are further modified with fluorescent probles and employed for interactions, as
ligands, with the T-cell antigen receptor on living cells.
The main model system employed for cell stimulation by a MIRR family member is that of mast
cells by the type 1 Fc-
receptor (Fc-
-RI). We have discovered that immobilization
of these receptors is one requirement for production of the stimulus. This most
probably is a more general constraint for most, if not all MIRRs and is rationalized
by the need for producing a "transdusosome", i.e. a nucleus of binding
sites on the receptors' cytosolic tails for downstream components of the signaling
cascade. We study the biochemical processes of the
FcRI coupling cascade, in particular
we pursue the control of the response to the FcRI by two different mechanisms:
The first is by a glycoprotein discovered in our lab and named Mast cell
Function-associated Antigen(MAFA) shown to have binding capacity to terminal manosides.
In MAFA's intracellular tail, a sequence is present which is analogous to that of
Immunoreceptors Tyrosine-based Inhibitory Motifs (ITIM). Recently, we have shown that two different
enzymes are mediating the inhibitory action: a protein tyrosine phosphatase (SHP-2)
and an inositol phospatase (SHIP). The inositol mechanism of these processes are investigated.
Another control mechanism of the cellular response to the Fc--RI discovered in our
lab is that exerted by the anaphylotoxin C3a and peptides derived from it.
Possible therapeutic uses of this discovery are being studied.
Electron Transfer Mechanisms Through Protein Matrices
The mechanism of electron transfer via polypeptide matrices is investigated in
two types of systems:
- 1) Using single-site mutations of the electron-carrier, single
blue copper protein azurin.
- 2) In the multi-centered redox enzymes, ascorbate oxidase,
nitrous oxide reductase as well as in iron or copper nitrite reductases.
List of Publications
