Download Chapter 15. Recognition of foreign molecules by the immune system

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 Unpublished results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