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Chapter 15. Recognition of foreign molecules by the immune system The clonal selection theory Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.299. The polypeptide chains of antibodies are divided into domains Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.301. Hypervariable regions (Complementarity Determining Regions) Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.302. Antibody diversity is generated by several different mechanisms ~1000 12 4 1 Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.302. Antibody diversity is generated by several different mechanisms intron Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.303. Enzymatic cleavage of immunoglobulin Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.304. All immunoglobulin domains have similar three-dimensional structures – Immunoglobulin fold The immunoglobulin fold is best described as two antiparallel β sheets packed tightly against each other Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.304. Comparison of the structures of the constant and variable domains of immunoglobulin Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.305. The hypervariable regions are clustered in loop regions at one end of the variable domain PRY-SPRY domain of TRIM72 - Immunoglobulin fold Park et al. Unpublished results The antigen-binding site is formed by close association of the hypervariable regions from both heavy and light chains Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.306. Packing of the four-stranded β sheets of the constant domains in Fab fragment of IgG Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.306-307. Packing of the two variable domains Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.307. Barrel arrangement of four β strands from each of the variable domains in Fab Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.308. Space-filling model of the hypervariable regions of an Fab fragment (six hypervariable regions) Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.308. The antigen-binding site binds haptens in crevices “a special class of antigen – a small molecule that reacts with a specific antibody, but cannot induce the formation of antibody unless bound to a carrier protein or other large antogenic molecule” Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.309. The antigen-binding site binds protein antigens on large flat surfaces Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.310. 20 x 30 Å Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.310. An IgG molecule has several degrees of conformational flexibility Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.312. Structures of MHC molecules have provided insights into the molecular mechanisms of T-cell activation MAJOR HISTOCOMPATIBILITY COMPLEX The Major Histocompatibility Complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and “antigen presentation”. The MHC molecules control the immune response through recognition of “self” and “non-self” and, consequently, serve as targets in transplantation rejection. The Class I and Class II MHC molecules belong to a group of molecules known as the Immunoglobulin Supergene Family, which includes immunoglobulins, T-cell receptors, CD4, CD8, and others. MHC molecules are composed of antigen-binding and immunoglobulin-like domains 2 macroglobulin Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.313. Recognition of antigen is different in MHC molecules compared with immunoglobulins Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.314. Peptides are bound differently by class I and class II MHC molecules Peptides derived from cytoplasmic proteins and class I transported into ER by transmembrane peptide pump class II Longer peptide & more H-bond Peptides derived from cell surface and extracellular proteins Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.315. T-cell receptors have variable and constant immunoglobulin domains and hypervariable regions Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.316. Structure of T-cell receptor Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.317. MHC-peptide complexes are the ligands for T-cell receptors Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.318. Many cell-surface receptors contain Ig-like domains - Fibronectin type III domain Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.319. “CD###: Cluster of Differentiation” Two domains of CD4 Branden & Tooze (1998), Introduction to protein structure, 2nd ed., p.319. Structural details and comparisons of the coreceptor-Lck complexes. In addition to metal coordination, hydrophobic cores stabilize the CD4 (A) and CD8 (B) complexes. In CD4, phosphorylation of Ser 408 (and to a lesser extent Ser415) promotes CD4 internalization. These residues are exposed in the complex, but the dileucine internalization motif is buried (leucines 413 and 414) (A). (B) The structured region of the CD8 complex is more modest; it consists of the Lck hairpin (red) and a 9-residue segment of CD8 (green) that contains the CxCP motif. (C) Superposition of the CD4 and CD8 complexes. The Zn 2+-binding cores of the two complexes, including the ß-hairpin region of Lck, superimpose well with an RMSD of 0.5 Å for mainchain atoms. The two helices found in the CD4 complex are absent in the CD8 complex, and the structured region of CD8 extends C-terminal to the CxCP motif, forming additional interactions that stabilize the complex. [Kim, P.W. et al. & Eck, M.J. (2003) Science 301, 1725-1728] SLAM (CD150, IPO-3) • SLAM (Signaling Lymphocyte Activation Molecule) • A cell surface glycoprotein of ~70 kDa • Belongs to the Immunoglobulin gene family (IgG1, kappa) • Homotypic interactions (Contributes bi-directionally to T-cell interactions with antigen presenting cells) SAP (SH2D1A, DSHP) • SAP (SLAM-Associated Protein) • Has been cloned in 1998 (Sayos et al & Terhorst, Nature; Coffey et al, Nature Genetics) • Consists of a single SH2 Domain (residues 1- 104) and a short 24 amino acid C-terminal tail • Relatively high-affinity for non-phosphorylated tyrosine residue • Expressed in T-lymphocytes, NK cells, and some B cells • Many missense and/or deletion mutations XLP (X-linked lymphoproliferative disease) XLP: X-linked Lymphoproliferative Disease • A familial disorder affecting males with a rapidly fatal course in response • • • • • to Epstein-Barr Virus (EBV) infection First reported in 1975 as Duncan’s disease (Purtilo et al, Lancet) Symptoms Fulminant infectious mononucleosis (50%) B-cell lymphomas (20%) Dys-gammaglobulinemia (30%) Aplastic anemia Vasculitis Pulmonary lymphomatoid granulomatosis Mortality rate is 100% at the age of 40 A gene (SAP) is deleted or altered in the XLP patients Gene map locus: Xq25 tongue, lateral border chest / trunk http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=-2016965227 Membrane SLAM FynT SAP FynSH3