Table 2.

Major restraints for receptor-mediated signaling imposed within the SCHOOL platform by the overall structural architecture and topology of receptors in combination with the major driving forces in receptor triggering and transmembrane signaling

Restraints	Functional significance
Sufficient interreceptor proximity in receptor dimers/oligomers	Two or more antigen/ligand-clustered receptors should be in sufficient proximity to each other to initiate interreceptor TM (SRs) and CYTO homointeractions between SRs or signaling subunits of MIRRs with subsequent formation of competent signaling oligomers
Correct (permissive for signaling) relative orientation of the receptors in receptor dimers/oligomers	Within two or more antigen/ligand-clustered receptors, receptor chains of SRs or particular signaling subunit(s) of MIRRs should be in correct orientation relative to each other to initiate CYTO homointeractions between SRs or between the signaling subunits of MIRRs with subsequent formation of competent signaling oligomers.
Long enough duration of the receptor-ligand interaction that generally correlates with the strength (affinity/avidity) of the ligand	Main protein-protein interactions involved in receptor triggering and TM signaling fall into a similar low/moderate (micromolar) affinity range. For this reason, the multivalent antigen/ligand-receptor contact should last long enough to bring two or more receptors in sufficient proximity and correct relative orientation toward each other and hold them together to promote the interreceptor CYTO homointeractions between SRs or between the signaling subunits of MIRRs, resulting in formation of competent signaling oligomers and thus initiating the downstream signaling cascade.
Sufficient lifetime of an individual receptor in receptor dimers/oligomers	Similarly to a restraint on duration of antigen/ligand-receptor contact, in order to initiate the downstream signaling cascade, a lifetime of an individual receptor in antigen/ligand-clustered receptors should be sufficient to promote the interreceptor CYTO homointeractions between SRs or between the signaling subunits of MIRRs.

Abbreviations: CYTO, cytoplasmic; SR, single-chain receptor; MIRR, multichain immune recognition receptor; SCHOOL model, signaling chain homooligomerization model; TM, transmembrane.