SCHOOL principles of receptor signaling. Single- (A) or multichain (B) receptor oligomerization (clustering) induced upon ligand binding outside the cell is translated across the membrane into protein oligomerization inside the cell with cytoplasmic homointeractions representing the major driving force of receptor triggering. For SRs (A), small solid black and gray arrows indicate specific inter-unit homointeractions between transmembrane and cytoplasmic domains, respectively. For MIRRs (B), small solid black and gray arrows indicate specific inter-unit hetero- and homointeractions between transmembrane and cytoplasmic domains, respectively. Circular arrow indicates ligand-induced receptor reorientation. Curved line depicts disorder of the cytoplasmic domains of MIRR signaling subunits (B). Phosphate groups are shown as dark circles. Abbreviation: SCHOOL, signaling chain homo-oligomerization. Adapted with permission from Sigalov AB. The SCHOOL of nature I. Transmembrane signaling. Self/Nonself 2010; 1.

Single-chain receptors (SRs). The extracellular portion of the receptors is on top and the cytoplasmic portion is on bottom. The lengths of the receptors as shown are only approximately to scale. The inset shows SR domain organization. Abbreviations: EpoR, erythropoietin receptor; G-CSF-R, granulocyte colony-stimulating factor receptor; TGFβ, transforming growth factor-beta; TNF, tumor necrosis factor; JAK, Janus kinase; EGFR, epidermal growth factor receptor; InsR, insulin receptor; IGF1R, insulin-like growth factor I receptor; IRR, insulin receptor-related receptor; PDGFR, platelet-derived growth factor receptor; CSF1R, colony-stimulating-factor 1 receptor; FGFR, fibroblast growth factor receptor; MuSK, muscle-specific receptor tyrosine kinase; Eph, ephrin; DDR, discoidin domain receptor; Flt1, KDR and Flt4, vascular endothelial growth factor (VEGF) receptors. Adapted with permission from Sigalov AB. The SCHOOL of nature I. Transmembrane signaling. Self/Nonself 2010; 1.

Multichain immune recognition receptors. Schematic presentation of the MIRRs expressed on many different immune cells including T and B cells, natural killer cells, mast cells, macrophages, basophils, neutrophils, eosinophils, dendritic cells and platelets. The inset shows MIRR assembly. Cytoplasmic domains of the MIRR signaling subunits represent a novel class of intrinsically disordered proteins and are shown to be dimeric. Curved line depicts protein disorder. Abbreviations: ITAM, immunoreceptor tyrosine-based activation motif; BCR, B-cell receptor; DAP-10 and DAP-12, DNAX adapter proteins of 10 and 12 kD, respectively; DCAR, dendritic cell immunoactivating receptor; GPVI, glycoprotein VI; ILT, Ig-like transcript; KIR, killer cell Ig-like receptor; LIR, leukocyte Ig-like receptor; MAIR-II, myeloid-associated Ig-like receptor; MDL-1, myeloid DAP12-associating lectin 1; NITR, novel immune-type receptor; NK, natural killer cells; SIRP, signal regulatory protein; TCR, T-cell receptor; TREM receptors, triggering receptors expressed on myeloid cells. Adapted with permission from Sigalov AB. The SCHOOL of nature I. Transmembrane signaling. Self/Nonself 2010; 1.

Intrinsically disordered cytoplasmic domain of T cell receptor ζ chain (ζ_cyt) does not fold upon binding to its unfolded (A) or folded (B) protein target. The ¹H-¹⁵N heteronuclear single quantum correlation (HSQC) spectra of ¹⁵N-labeled ζ_cyt at 298 K (A) or 283 K (B) in the absence (blue) or presence (red) of its interacting partner, another ζ_cyt molecule (A) or the well-folded and ordered SIV Nef protein (B). In both scenarios, a new, previously unobserved NMR phenomenon, the lack of significant changes in chemical shift and intensity upon a specific protein complex formation, has been reported.9,11,60 Cross-peak positions of the SIV Nef interaction domains (SNIDs) residues are marked to highlight the lack of chemical shift changes for these residues upon binding to Nef. Adapted with permission from Sigalov AB, Zhuravleva AV, Orekhov VY. Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form. Biochimie 2007; 89:419–21 and Sigalov AB, Kim WM, Saline M, et al. The intrinsically disordered cytoplasmic domain of the T cell receptor zeta chain binds to the Nef protein of simian immunodeficiency virus without a disorder-to-order transition. Biochemistry 2008; 47:12942–4.

Binding of an intrinsically disordered protein (IDP) to its target. Upon binding, an IDP may (A) or may not (B) fold on its interacting partner. (A) Binding of an IDP to another IDP or to a folded and well-ordered protein is coupled to secondary structure induction (left upper). In this widely observed scenario, interactions at the binding interface that mediate specific complex formation represent the interactions between folded domains (induction of helices is shown for illustrative purposes). Helical structure induction upon binding of an IDP to micelles or unstable lipid bilayers (left bottom) has been also widely reported.35,36,53,54 (B) Binding of an IDP to another IDP or to a folded and well-ordered protein is not accompanied by a disorder-to-order transition (right upper). In the recently discovered surprising scenario of IDP homo-oligomerization,9,11 interactions at the binding interface that mediate a specific oligomer formation represent the interactions between disordered domains making these interactions unusual and intriguing. The lack of secondary structure induction upon binding of an IDP to a folded and well-ordered protein has been also reported.60 Binding of an IDP to stable lipid bilayers without a disorder-to-order transition (right bottom) has been also demonstrated.53 Images were created using PyMol (www.pymol.org) from PDB file 1AVV for the HIV-1 Nef core domain (shown as an example of a folded interacting partner) and using arbitrary idealized structural elements to represent the ensemble of unfolded conformations of an IDP. Polar head groups and hydrophobic tales of detergent and lipid molecules are denoted by gray filled circles and lines, respectively. Adapted with permission from Sigalov AB. Protein intrinsic disorder and oligomericity in cell signaling. Mol Biosyst 2010; 6:451–61 and Sigalov AB, Hendricks GM. Membrane binding mode of intrinsically disordered cytoplasmic domains of T cell receptor signaling subunits depends on lipid composition. Biochem Biophys Res Commun 2009; 389:388–93.