細胞學
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(2) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • History of studies on intracellular signal transduction – Dr. Earl W. Sutherland: The Nobel Prize in Physiology and Medicine 1971; epinephrine/glycogen metabolism 訊息接收 訊息轉換及放大. 細胞內訊息傳遞的放大作用. 2.
(3) 細胞內訊息傳遞 (Intracellular Signaling Transduction) Chemical signals for intercellular communication – Endocrine, paracrine, and autocrine – Water-soluble or lipid-soluble messengers – Interactions between messengers (ligand) and receptor:. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Characteristics and functions of receptors 1. Intracellular receptors: most in nucleus • ligand (lipid-soluble; pass plasma membrane by diffusion)+ receptor = transcription factor: recognize specific DNA sequence (enhancer). 3.
(4) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Characteristics and functions of receptors 1. Intracellular receptors: most in nucleus 2. Plasma membrane receptors: A.G protein (guanine-binding protein) -coupled receptors: • Receptors contain seven membranespanning regions: 7 α−helix. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Characteristics and functions of receptors. 1. Intracellular receptors: most in nucleus 2. Plasma membrane receptors: A. G protein-coupled receptors (GPCR): – Receptors – G protein » large heterotrimeric: Gα (binding with GTP or GDP, and hydrolizing GTP), Gβ, and Gγ. 4.
(5) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Characteristics and functions of receptors. 1. Intracellular receptors: most in nucleus 2. Plasma membrane receptors: A. G protein-coupled receptors (GPCR): – Receptors: – G protein » large heterotrimeric: » small monomeric: Rho, Ras, etc. – Dr. Martin Rodbell and Dr. Alfred Gilman: Nobel Prize in Medicine and Physiology 1994 on G protein study.. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Characteristics and functions of receptors 1. Intracellular receptors: most in nucleus 2. Plasma membrane receptors: A. G protein-coupled receptors: B. Tyrosine kinase (TK) receptors: - Cytoplasmic portion contains tyrosine kinase and tyrosine residue: receptor aggregation and auto-phosphorylation - Recruited cytosolic proteins: having SH2 (Src Homology) domain to bind with phosphorylated tyrosine - Activated PLCγ to initiate IP3 pathway: PLCγ also have SH2 domain. 5.
(6) Tyrosine kinase (TK) receptors. 訊息接收. 訊息轉換及放大. 6.
(7) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers: – water-soluble signals can not pass the plasma membrane 1.Cyclic AMP (cAMP):. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers: 1. Cyclic AMP (cAMP): - Adenylate (adenylyl) cyclase activated by Gsα can convert ATP to cAMP:. 7.
(8) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers: 1. Cyclic AMP (cAMP): • Adenylate cyclase converts ATP to cAMP: • Protein kinase A (PKA): cAMP-dependent protein kinase. • cAMP-specific phosphodiesterase: cAMP → AMP. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers:. 1. Cyclic AMP (cAMP): 2. Inositol-1,4,5-trisphosphate (InsP3; IP3) and diacylglycerol (DAG): inositol-phospholipidcalcium pathway – Phospholipase C (PLC): PLCβ activated by G protein – Phosphatidylinositol-4,5-bisphosphoate (PIP2) → IP3 + DAG – IP3: bind to calcium channel on ER or mitochondria to release Ca+2. 8.
(9) Inositol-phospholipid-calcium pathway. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers: 1. Cyclic AMP (cAMP): 2. Inositol-1,4,5-trisphosphate and diacylglycerol: – Phospholipase C (PLC): – PIP2 → IP3 + DAG – Protein kinase C (calcium-dependent protein kinase; PKC): activation by DAG – Calmodulin: Ca+2-binding protein – Calcium ions: [Ca+2]i in resting cells is around 10-6 ~10-7M – calcium channel or calcium pump on plasma membrane, ER or mitochondria. 9.
(10) calcium channel or calcium pump on plasma membrane, ER or mitochondria. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signal transduction by second messengers: 1. Cyclic AMP (cAMP): 2. Inositol-1,4,5-trisphosphate and diacylglycerol : 3. Other messengers in other pathways: – Apoptosis – Cell migration – Cell division. 10.
(11) 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Protein activation: phosphorylation by protein kinase and dephosphorylation by phosphotase • Signaling regulation – Adrenergic receptor • epinephrine → β adrenergic receptor → cAMP → glycogen degradation • norepinephrine → α adrenergic receptor → IP3/Ca+2 → muscle contraction. 細胞內訊息傳遞 (Intracellular Signaling Transduction) • Signaling regulation – Adrenergic receptor – Platelet activation • Exposed collagen on wound tissue → collagen receptor on platelets → G protein → phospholipase A2 → arachidonic acid → cyclooxygenase → thromboxane A2 (prostaglandin)→ thromboxane A2 receptor on platelet → G protein • Aspirin can reduce heart attack by inhibiting cyclooxygenase: slow platelet activation and recruitment. 11.
(12) 細胞膜 (Plasma Membrane) • Structure of plasma membrane: • Functions of plasma membrane:. 細胞膜 (Plasma Membrane) • Fluidity of plasma membrane:. 12.
(13) 細胞膜調控 (Membrane Regulation) • Transportation cross the plasma membrane:. 細胞膜調控 (Membrane Regulation) • Transportation cross the plasma membrane:. 13.
(14) 細胞附著 (Cell Adhesion) • Cell-to-cell and cell-tomatrix are the most important phenomena of a multi-cellular life form.. 細胞附著 (Cell Adhesion) • Cell-cell adhesion: for intercellular communication and transportation – Fertilization: sperm-egg, yeast mating, etc. – Embryogenesis: induction, morphogenesis, etc – Metastasis of cancer cells and NK cell killing – Neural-neural and neural-muscular junction – Immune responses: lymphocyte homing, Ab formation, phagocytosis, etc. – Pathogen (bacteria, viruses, and fungi, etc.) infection. 14.
(15) 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion. – Cell junctions: permanent structures A. Tight junction: Continuous belts around epithelia to prevent leaking of molecules or microbial invasion. B. Desmosome: intermediate filament (tonofilament):. 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion – Cell junctions: A. Tight junction: B. Desmosome: C. Gap junction: a direct chemical or electrical communication. 15.
(16) 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion – Cell junctions: permanent structures A. Tight junction: B. Desmosome: C. Gap junction: – Connexon forms a 1.5 nm diameter channel: <1200 daltons – The fastest cell communication: in nerve (electrical coupling), smooth muscle and heart muscle. 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion – Cell junctions: permanent structures – Cell adhesion molecules (CAMs): dynamic structures • Cadherin: Ca+2dependent binding, cadherin - catenin (α, β, γ) - actin. - Adhesion belt:. 16.
(17) 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion – Cell junctions: permanent structures – Cell adhesion molecules (CAMs): dynamic structures A.Cadherin: B. Immunoglobulin superfamily: Ca+2independent, single-passed transmembrane domain. - TCR (T cell receptor), MHC, CD4, CD8, etc. C. Selectin: lectin-like domain (binding with specific CHO), Ca+2-dependent.. Extravasation of leukocytes. 17.
(18) 細胞附著 (Cell Adhesion) • Molecules involved cell-cell adhesion – Cell junctions: permanent structures – Cell adhesion molecules (CAMs): A.Cadherin: B. Immunoglobulin superfamily: C. Selectin: D. Integrin: transmembrane heterodimer - α (binding site) and β subunit - Some recognize RGD (arginine-glycineaspartate)-peptide, Ca+2/Mg+2-dependent - Focal adhesion: integrin - vinculin - talin actin. 細胞附著 (Cell Adhesion) Cell-matrix adhesion: • Extracellular matrix (ECM) is constituted by variety of versatile polysaccharides and proteins. – Spermatogenesis and oogenesis: – Embryogenesis: – Epithelial cell differentiation: – Wound healing: – Decellularization and recellularization of tissues and organs – Settle-down of marine invertebrate larva:. 18.
(19) 細胞附著 (Cell Adhesion) • Molecules. involved into cell-matrix interactions: – Collagen: most abundant protein in your body to provide tensile strength • Connective tissues: type I (in skin, bones and tendons), type II (in cartilage), type III (in skin, and tendons), and type IV in basal laminae • Aging: collagen becomes increasingly cross-linked and inflexible.. 細胞附著 (Cell Adhesion) • Molecules involved into cell-matrix interactions: – Collagen: – Proteoglycan (PG): hydrophilic, gel-like network • Glycosaminoglycans (GAGs): unbranched polysaccharide chains composed of repeating disaccharide units) – Fibronectin (from fibroblast): RGDS sequence – Laminin: the basal lamina specific protein • YIGSR (tyrosine-isoleucine-glycine-serinearginine) sequence for laminin receptor. 19.
(20) Model of the Basal Lamina. 細胞骨架 (Cytoskeleton) • The general functions of cytoskeletons: 1.Protection and shape maintenance: 2.Spatial distribution: compartmentation 3.Transportation of membrane-bound organelles, mRNA, etc.: 4.Cell motility and contraction:. 20.
(21) 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton – Microtubule: α-tubulin and β-tubulin → protofilament → hollow tube – Microtubule organization center (MTOC): initiate MT assembly – in centrosome: MTs form mitotic spindle – in basal body: MTs form axon, cilia and flagella. 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton – Microtubule: tubulin • Microtubule organization center (MTOC): • Microtubule-associated protein (MAPs): – Motor MAPs: kinesin (to "+" end) and dynein (to "-" end).. 21.
(22) 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton. – Microtubule: • Microtubule organization center (MTOC): • Microtubule-associated protein (MAPs): • Cilia and flagella beating: axoneme (9+2). 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton – Microtubule: – Microfilament (MF): G-actin → F-actin → two interwined chains – α-actin (in muscle cells: sliding-filament model) as well as β-actin and γ-actin (in nonmuscle cells). 22.
(23) 細胞骨架 (Cytoskeleton) • Structural. elements of the cytoskeleton – Microtubule: – Microfilament (MF): actin A. Cell cortex: in dense networks located beneath the plasma membrane B. Focal adhesion plaques (focal contacts): stress fiber. 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton – Microtubule: – Microfilament (MF): actin A. Cell cortex: B. Focal adhesion plaques (focal contacts): C. Cytoplasmic streaming or amoeboid movement: - Gel-to-sol transition and filopodia formation: D. Cytokinesis: contractile ring (actin and myosin II) E. Sperm-egg fertilization: acrosome reaction. 23.
(24) Sperm-egg fertilization: acrosome reaction. 細胞骨架 (Cytoskeleton) • Structural elements of the cytoskeleton – Microtubule: – Microfilament (MF): – Intermediate filament (IF): real cytoskeleton • Tissue specificity: IF typing - differentiate marker and cancer diagnosis. 24.
(25) 蛋白質分項及運輸 (Protein Sorting and Transportation) • The proteins secretory pathway: RER → Golgi → secretory vesicles → plasma membrane → cell exterior. 蛋白質分項及運輸 (Protein Sorting and Transportation) • Signal hypothesis by Blobel and Dobberstein in 1975: All mRNA initially bind with free ribosomes in cytoplasm 1.The N-terminus of the growing polypeptide without signal sequence (contain a stretch hydrophobic a.a.): the synthesized proteins are transported to nucleus, mitochondria, chloroplasts, and peroxisomes. 2.The N-terminus of the growing polypeptide with signal sequence: The associated ribosomes are targeted to the ER, and the synthesized proteins are transported to plasma membrane, lysosomes and secretory vesicles.. 25.
(26) 蛋白質分項及運輸 (Protein Sorting and Transportation) • Translation in ER: 1. Signal sequence bind to signal recognition particle (SRP): Translation pauses. 2. The complex (SRP, ribosome, and growing peptide) adheres to the ER membrane (SRP binds to SRP receptor). 3. Ribosome binds with protein translocation channel (Sec61) causing channel open. 4. Signal sequence insert into the channel and translation resumes. 5. Signal sequence cleaved by signal peptidase.. Protein Transportation to ER. 26.
(27) 蛋白質分項及運輸 (Protein Sorting and Transportation) • Translation in ER: – Multiple membranespanning protein: an alternating series of internal signal sequences and stoptransfer sequences.. 蛋白質分項及運輸 (Protein Sorting and Transportation) • Translation in ER: – Multiple membrane-spanning protein: – Protein can be anchored in the ER membrane by internal signal sequences that are not cleaved by signal peptidase:. 27.
(28) 蛋白質分項及運輸 (Protein Sorting and Transportation) • Translation in ER: – Multiple membrane-spanning protein: – Protein can be anchored in the ER membrane by internal signal sequences that are not cleaved by signal peptidase: – Protein glycosylation: N-linked glycosylation in ER -14 sugars are added to the growing polypeptide. – Glycosylphosphatidylinositol (GPI) anchors contain two fatty acid chains, inositol, oligosaccharide, and ethanolamine:. N-linked glycosylation in ER. 28.
(29) 蛋白質分項及運輸 (Protein Sorting and Transportation) • Export of proteins and lipids from the ER – KDEL (Lys-Asp-Glu-Leu) sequence at Cterminus: retain in ER lumen – KKXX (Lys-Lys-X-X) sequence at C-terminus: retention on ER membrane. 蛋白質分項及運輸 (Protein Sorting and Transportation) • Organization of the Golgi – Golgi: The cis (entry) face is convex and the trans (exit) face is concave.. 29.
(30) 蛋白質分項及運輸 (Protein Sorting and Transportation) • Organization of the Golgi – Golgi: – Protein glycosylation within the Golgi 1. Modification for secretion or plasma membrane N-linked glycoprotein: • Membrane protein: adding sialic acid • Secretion (lysosomal) protein: adding mannose-6-phosphate (M-6-P). 2. O-linked glycoprotein:. Protein glycosylation within the Golgi. 30.
(31) 細胞週期及凋亡 (Cell cycle and apoptosis) - Phase of the cell cycle: - G (gap)1 → S (synthesis) → G2 → M (mitosis) ↘ G0 ↗. 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulation of the cell cycle: - A cell cycle regulatory points in many types of cells occurs late in G1: - Restriction point (regulation by growth factors in animal cells) and START (regulation by nutrients in yeasts). 31.
(32) 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulation of the cell cycle: - A cell cycle regulatory points in many types of cells occurs late in G1: - Cell cycle checkpoints - At G1: damaged DNA increases the level of p53. - p53: the gene of p53 frequently mutated in human cancers. 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulation of the cell cycle: - A cell cycle regulatory points in many types of cells occurs late in G1: - Cell cycle checkpoints - At G1: damaged DNA increases the level of p53. - At G2: damaged or unreplicated DNA - At M phase: chromosome mis-alignment. 32.
(33) 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulators of cell cycle progression – MPF (maturation promoting factor): A dimmer of cdc2 and cyclin B - cdc (cell division cycle)2: protein kinase - cdc25: protein phosphotase. 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulators of cell cycle progression - MPF (maturation promoting factor): - cdc2: - cdc25: - cyclin: accumulation throughout interphase and then rapid degradation toward the end of each mitosis. 33.
(34) 細胞週期及凋亡 (Cell cycle and apoptosis) - Regulators of cell cycle progression - MPF (maturation promoting factor): - cdc (cell division cycle)2: - cdc25: - cyclin: - Families of cyclins and cyclindependent kinase - cyclin B, cyclin D, G1cyclin (Cln), cdk (cyclin-dependent kinase), CAK (cdk-activating kinase), CKI (cdk inhibitor), …. 細胞週期及凋亡 (Cell cycle and apoptosis) - The events of M phase - Stages of mitosis: prophase → metaphase → anaphase → telophase. 34.
(35) 細胞週期及凋亡 (Cell cycle and apoptosis) - The events of M phase - Stages of mitosis: - MPF and progression to metaphase: - chromatin condensation: phosphorylation of histone H1 - nuclear envelope breakdown: phosphorylation of lamin fragmentation of Golgi and ER. 細胞週期及凋亡 (Cell cycle and apoptosis) - The events of M phase - Stages of mitosis: - MPF and progression to metaphase: - chromatin condensation: - nuclear envelope breakdown: - fragmentation of Golgi and ER - spindle formation: centromere-kinetochoremtotic spindle (microtubule). 35.
(36) 細胞週期及凋亡 (Cell cycle and apoptosis) - Apoptosis: DNA fragmentation, cytoplasm shrinkage, and membrane change. 細胞週期及凋亡 (Cell cycle and apoptosis) - Apoptosis: - Programmed cell death: a normal physiological form of cell death that plays a key role in the maintenance of adult tissues and in embryonic development. - maintenance of adult tissues: blood cells - maintenance in embryonic development: metamorphosis, nervous system, immune system - Death signal →→ Bcl-2 (Ced-9) →→ ICE (Ecd-3) →→ apoptosis. 36.
(37) 細胞週期及凋亡 (Cell cycle and apoptosis) - Apoptosis: - Programmed cell death: - Damaged cells without lysis or damage to neighboring cells - Virus-infected cells: - DNA damaged cells: UV, heavy metal, etc.. 37.
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