考研：细胞生物学六章基质与内膜(中)课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,考研资料：北京大学细胞生物学第六章基质与内膜(中),4. The structure and functions of Lysosomes,A.,Characteristics of Lysosomes, Lysosome is a heterogenous organelle:,Primary lysosomes,Second lysosomes,heterophagic,autophagic,Residual body,Primary Lys,.,Second Lys,表,1.,神经鞘脂,贮,积病,疾病,缺失酶类,主要贮积底物,后果,GM1,神经节苷脂贮积症,GM1,-,半乳糖苷酶,神经节苷脂,GM1,智力迟钝，肝脏肥大，骨骼受累，,2,岁前死亡,泰萨二氏病,己糖胺酶,A,神经节苷脂,GM2,智力迟钝，失明，,3,岁前死亡,法布莱氏病,-,半乳糖苷酶,A,三己糖神经酰胺,皮疹，肾功能丧失，下肢疼痛,山霍夫氏病,己糖胺酶,A,和,B,神经节苷脂,GM2,和红细胞糖苷酯,与泰萨氏疾病症状相似，但发展更快,高歇氏病,葡糖脑苷酯酶,葡糖脑苷脂,肝脏和脾脏肿大，长骨腐蚀，只在婴儿期发生智力迟钝,尼,-,皮二氏病,鞘磷脂水解酶,鞘磷脂,肝脏和脾脏肿大，智力迟钝,Farbers,脂肪肉芽肿病,神经酰胺水解酶,神经酰胺,疼痛性与退行性的关节变形，皮肤瘤，几年内死亡,Krabbes,病,半乳糖脑苷酯酶,半乳糖脑苷脂,髓磷脂缺失，智力迟钝，,2,岁前死亡,脑硫脂沉积,芳基硫酸酯酶,脑硫脂,智力迟钝，前十年死亡,D. Biogenesis of Lysosomes,Figure6-23,The transport of newly synthesized lysosomal hydrolases to lysosomes.,The precursors of lysosomal hydrolases are covalently modified by the addition of mannose 6-phosphate in the,CGN,. They then become segregated from all other types of proteins in the,TGN,because a specific class of transport vesicles budding from the,TGN,concentrates mannose 6-phosphate-specific receptors, which bind the modified lysosomal hydrolases. These vesicles subsequently fuse with late endosomes. At the low pH of the late endosome the hydrolases dissociate from the receptors, which are recycled to the Golgi apparatus for further rounds of transport. In late endosomes the phosphate is removed from the mannose on the hydrolases, further ensuring that the hydrolases do not return to the Golgi apparatus with the receptor.,Mannose 6-phosphate residues target proteins to lysosomes,Targeting of soluble lysosomal enzymes to endosomes and lysosomes by M-6-P tag,Phosphorylation of mannose residues on lysosomal enzymes catalyzed by,two enzymes,Recognition site binds to Signal patch,GlcNAc phosphotransferase,phosphodiesterase,Figure 6-40. The mannose 6-phosphate (M6P) pathway, the major route for targeting lysosomal enzymes to lysosomes.,Precursors of lysosomal enzymes migrate from the rER to the,cis,-Golgi where mannose residues are phosphorylated. In the,TGN, the phosphorylated enzymes bind to M6P receptors, which direct the enzymes into vesicles coated with the clathrin. The clathrin lattice surrounding these vesicles is rapidly depolymerized to its subunits, and the uncoated transport vesicles fuse with late endosomes. Within this low-pH compartment, the phosphorylated enzymes dissociate from the M6P receptors and then are dephosphorylated. The receptors recycle back to the Golgi, and the enzymes are incorporated into a different transport vesicle that buds from the late endosome and soon fuses with a lysosome. The sorting of lysosomal enzymes from secretory proteins thus occurs in the,TGN, and these two classes of proteins are incorporated into different vesicles, which take different routes after they bud from the Golgi.G. Griffiths et al.,Cell,52,:329; S. Kornfeld,Annu. Rev. Biochem.,61,:307; and G. Griffiths and J. Gruenberg,Trends Cell Biol.,1,:5,5. Protein Sorting,Overview of sorting of nuclear-encoded,proteins in eukaryotic cells,Proteins are imported into organelles by three,mechanisms:,Gated Transport: Transport through nuclear pores,Transmembrane,transport: ER,Mit,Chl, Per,Vesicular transport: ER-,Golgi-PM-Lys,Endosome,Road map of protein sorting,Protein sorting: Protein molecules move from the,cytosol,to their target organelles or cell surface directed by the,sorting signals,in the proteins.,Signal peptides and Signal patches,Figure6-8,Two ways that a sorting signal can be built into a protein.,(A) The signal resides in a single discrete stretch of amino acid sequence, called a,signal peptide,that is exposed in the folded protein. Signal peptides often occur at the end of the polypeptide chain, but they can also be located elsewhere. (B) A,signal patch,can be formed by the juxtaposition of amino acids from regions that are physically separated before the protein folds; alternatively, separate patches on the surface of the folded protein that are spaced a fixed distance apart could form the signal.,Gated transport:,Through gated poresNuclear pores;,Nuclear localization signal (NLS);,Folded and assembly form to transport.,Transmembrane transport,ER signal sequence,Mit, Chl, Per: Leader sequence;,Through translocon on the membrane;,Single and Unfold form;,Helped by molecular chaperons,Vesicular transport,Budding, transporting, docking and at last fusion with target membrane;,Assembly coated proteins on the vesicles (Clathrin, COPII and COPI);,Only Properly folded and assembled proteins;,The orientation of transported proteins and lipids is not changed during transporting.,