덕성여자대학교 약학과 조효선 교수 -...
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덕성여자대학교 약학과
조효선 교수
Fig. 4.5. Rearrangement of V, D, J gene segments guided by RSSs RSSs : recombination signal sequences 재조합 신호서열 Heptamer(conserved)--spacer(12 or 23 bp ; nonconserved)--nonamer(conserved) 12/23 rules; gene segment with 12bp spacer only join to 23bp spacer e.g., in heavy chain rearragement, VH can not join JH gene segment directly
Chapter 8;항원수용체 (Antigen receptor)
Chapter 8;항원수용체 (Antigen
receptor)
Fig. 4.7. Enzymatic steps in RAG-dependent V(D)J rearrangement RAG1,2 ; V(D)J recombinase, cut RSSs, create hairpin
Ku70:Ku80 ; bind to hairpin
DNA-PK, DNA dependent protein kinase, Artemis ; open the hairpin (cut at random site)
TdT, terminal deoxynucleotidyl transferase ; add nucleotides randomly
DNA ligase; ligate DNA ends
- Rearrangement of V, (D), J gene segments = V(D) J recombination Defect(mutation) in RAG ; SCID(severe combined immune deficiency) in mice Omenn syndrome in human - Combinatorial diversity : multiple different copies of each type of gene segment different combinations of gene segments many possible different combinations of H and L chain V regions e.g., V1-D2-J1, V2-D1-J6 - Junctional diversity ; addition or subtraction of nucleotides at the joints by recombination process e.g., N-nucleotides
Chapter 8;항원수용체 (Antigen receptor)
Fig.4.18. Coexpression of IgD and IgM is regulated by RNA processing
- IgD & IgM coexpressed on the surface of mature B cells - primary mRNA transcript that differentially spliced to distinct mRNA molecule e.g., VDJ exon linked to Cμ exon to encode μ heavy chain
Chapter 8;항원수용체 (Antigen receptor)
성숙 B 세포
IgD
IgM
미성숙 B 세포
IgM
골수 림프절 Ag
Fig. 4.21. Secondary diversification of the antibody (항체의 2차 다양성)
- occurs in activated B cells - driven by antigen 1. Somatic hypermutation (체세포 과돌연변이) ; mutations introduced to heavy c
hain or light chain V regions, altering the affinity of the antibody for its antigen
2. Gene conversion ;rearranged V region is modified
by the introduction of sequences derived from V gene segment
3. Class switching(클래스 전환) ;initial μ heavy chain C regions ar
e replaced another isotype, modifying effector activity, not antigen specificity
Chapter 8;항원수용체 (Antigen receptor)
B cell signaling
Chapter 6. Signaling through immune system receptors (From Janeway’s immunobiology, 7ed)
By Cell signaling technology
1
2?
3 ?
4
B(T) 세포
Ag
Chapter 6. Signaling through immune system receptors
General principles of signal transduction
1) Extracellular signal
2) Transmembrane receptor
3) Intracellular signaling pathway (signal transduction)
4) Alteration of gene expression
1
2?
3 ?
4
B(T) 세포
Ag
Fig. 6.1. two types of receptors that signal through protein kinases - Phosphorylation occurs in tyrosine, serine, threonine
- two types of receptors for kinase activity : part of receptor or associate with receptor
Chapter 6. Signaling through immune system receptors
Fig. 6.3 Assembly of signaling complexes is mediated by scaffold and adaptor proteins
- Scaffold proteins (larger) : no enzyme activity, recruits many proteins - Adaptor proteins (smaller) : link two proteins together
SH2, SH3 : Src Homology domain
Fig. 6.6. Recruitment of signaling proteins
PIP2
PI 3-kinase PIP3
AKT, ITK binds to PIP3
PI 3-kinase : phosphatidylinositol 3-kinase PIP2 : phosphatidylinositol 4,5-biphosphate PIP3 : phosphatidylinositol 3,4,5-trisphosphate
p + p + p + sugar(당) + guanine(nucleic acid) GTP
p + p + sugar(당) + guanine(nucleic acid) GDP
GTPase
From WIKIPEDIA
From WIKIPEDIA
GEFs : guanine nucleotide exchange factors GAPs : GTPase-activating proteins e.g., Ras family (Ras, Rac, Rho, Cdc42) cell proliferation
Fig. 6.5. small G proteins = GTP-binding proteins = small GTPases
GDP-Gproteins
(inactive) GTP GAPs GEFs GDP
GTP-Gproteins (active)
PIP3 PIP2
From WIKIPEDIA From WIKIPEDIA
PI 3-kinase
Fig. 6.7. membrane lipid rafts
Small Sphingolipid + Cholesterol rich membrane rigidity 25~50% of plasma membrane dynamic structures most signaling occurs receptors move into lipid rafts GPI : glycosylphosphatidylinositol
Fig. 6.8. Terminating signaling = Dephosphorylation, Protein degradation
SHP : protein phosphatase Cbl : ubiqutin ligase