Novel Mechanistic Insights into Viral Modulation of Immune Receptor Signaling

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

“…117 Within the SCHOOL model, distinct TCR signaling is achieved through the ζ and CD3 signaling oligomers, 52,71,72,74,75 and interreceptor TM interactions represent not only a promising therapeutic target but also an important point of viral attack. 72,73,133,137 The TCR core peptide (CP), a synthetic peptide corresponding to the sequence of the TCRα transmembrane domain, is capable of inhibiting antigen-mediated T-cell activation, whereas T-cell activation via anti-CD3 antibodies is not affected by CP. 138 However, despite extensive studies, the mode of action of this clinically relevant peptide had not been elucidated until 2004 when the SCHOOL model was first introduced.…”

“…Briefly, CP and FP compete with TCRα for binding to CD3δε and ζζ, resulting in functional disconnection of these subunits. 72,133,137,140 In summary, our current understanding of TCR signaling, together with the lessons learned from the viral patho genesis, 2,73,75,133,134,137 can be used not only for further fundamental research but also for rational drug design.…”

The SCHOOL of nature: I. Transmembrane signaling

“…in addition, the signaling oligomers formed can sequentially interact with the signaling subunits of nonengaged TCrs resulting in formation of higher-order signaling oligomers, thus amplifying and propagating the activation signal (not shown to the MIRR-mediated processes involved in viral pathogenesis. 4,98,129,221,222,[338][339][340] Interestingly, the model suggests a molecular explanation for the apparent discrepancies in in vitro and in vivo activities of cell-permeable chemical inducers of dimerization. [341][342][343] In 1993, it was reported that in vitro chemically induced dimerization/oligomerization of the TCRζ CYTO domain results in T cell activation, as measured with a reporter gene assay.…”

“…388 Similarly to the TCr-CP, the Hiv-1 gp41 FP disrupts TCrα-CD3δε and TCrα-ζ 2 TM interactions resulting in dissociation of these signaling subunits from the remaining complex, and thus preventing the formation of signaling oligomers upon Ag but not Ab stimulation and, consequently, inhibiting Ag-but not Ab-mediated T cell activation. 4,221,339 responses. 351 Considering that in the TCR-CD3-ζ 2 complex, the TCRβ TM domain is critical for interaction with the CD3γε signaling heterodimer, 33 one can suggest that in a mutant TCR, the association of the CD3γε with the TCRβ chain is impaired.…”

Cells diversify transmembrane signaling through the controlled chaos of protein disorder

“…Recent studies [26][27][28][29][30] suggest that in order to establish a successful infection, viruses have evolved the strategy to attack this Achilles' heel of MIRRs and disrupt functional coupling between two aspects of receptor machinery: recognition and signaling. This allows viruses to cheat the immune system and enter response to different ligands is higher with the more different signaling subunits (or ITAMs on the same subunit) the MIRR complex has.…”