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BSC 300, Week 8

by: Ashley Bartolomeo

BSC 300, Week 8 BSC 300

Ashley Bartolomeo
GPA 3.9

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Notes on second half of chapter 8
Cell Biology
John yoder
Class Notes
Cell, Biology
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This 8 page Class Notes was uploaded by Ashley Bartolomeo on Thursday October 6, 2016. The Class Notes belongs to BSC 300 at University of Alabama - Tuscaloosa taught by John yoder in Fall 2016. Since its upload, it has received 3 views. For similar materials see Cell Biology in Biology at University of Alabama - Tuscaloosa.


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Date Created: 10/06/16
Chapter 8 Cytoplasmic Membrane Systems: Structure, Function and Membrane Trafficking Part 2 The Golgi Complex  A system of flattened, disk like cisternae with dilated rims and associated vesicles and tubules  Principle roles in protein/lipid modification, sorting, packaging and delivery  Divided into several functionally distinct compartments arranged in an axis from cis, to medial to trans  The cis face of the Golgi faces the ER; the trans face is on the opposite side of the stack  Cis-Golgi network is a sorting station, distinguishing proteins that need to be shipped back to ER from those that will be distributed throughout the endomembrane system  Trans-Golgi network a packaging station where proteins are segregated into different types of membrane enclosed vesicles for delivery to the plasma membrane or organelles  As proteins progress from cis to trans network they are modified and processed The Golgi Complex: CGN to TGN  Regional differences in membrane composition across the Golgi stack visualized by different markers:  1) Osmium tetroxide in the cis cisternae  2) Mannosidase II in the medial cisternae  3) Nucleotide diphosphate in the trans cisternae  The complex is not uniform from one end to the other. The various Golgi regions have different compositions of enzymes that modify and process proteins differently  Newly synthesized proteins leave the ER via transport vesicles through the ERGIC which fuse with the cis-Golgi Network (CGN). Proteins pass through the medial to the trans-Golgi network (TGN), and along the way are further modified, depending on protein function and final destination Glycosylation in the Golgi Complex  While N-linked glycosylation begins in the ER, O-linked glycosylation occurs exclusively in the Golgi. O-linked glycosylation: Addition of NAG sugar to the –OH group of specific serine and threonine residues of certain proteins. Further modified as proteins matures in the Golgi  Glycosyltransferase enzymes within the Golgi stacks modify the core carbohydrate chains of N-linked glycosylation producing species-, individual- and cell-specific glycosylation patterns  For N-linked glycosylation this first involved pruning of the mannose sugars followed by protein specific addition of other monomer The Extracellular Space Structure of a Proteoglycan Complex  Proteoglycans- protein polysaccharide complex, with a core protein attached to glycosaminoglycans (GAGs) o Each GAG chain has a repeating disaccharide structure o Extremely acidic due to presence of both sulfate and carboxyl groups Movement Through the Golgi Complex  Two competing models for the movement of materials through the Golgi Complex 1. Cisternal maturation model: each cistern “matures” as it moves from the cis face to the trans face. Cis face forms from fusion of vesicles arriving from ER and cisternae mature as they progress toward the trans face 2. Vesicular transport model: cargo is shuttled from the CGN toward the TGN in vesicles. The actual stacks remain relatively unchanged  Current model is a combination of the two. Cisternae mature and progress from cis to trans side of the complex. Transport vesicles move in a retrograde fashion (from trans toward medial and cis) delivering Golgi resident proteins (enzymes) back to appropriate locations Types of Vesicular Transport and Functions  Materials are carried between endomembrane compartments via coated vesicles: membraneous sacs surround by specific protein networks  Protein coats have two functions: o Curve membrane, forming spherical vesicles that detach from cisternae o Select components to be carried by vesicle: cargo (proteins/lipids) as well as targeting and docking proteins Types of Vesicle Transport  COPII coated vesicles – move materials from the ER “forward” to the ERGIC and Golgi complex (anterograde)  COPI coated vesicles – move materials from ERGIC and Golgi “backward” to ER, or from the trans Golgi to the cis Golgi cisternae (retrograde)  Clathrin coated vesicles – move materials from TGN to endosomes, lysosomes and become secretory granules destined for plasma membrane (anterograde). Also import proteins from the plasma membrane (retrograde) A Brief Introduction to G-Proteins  G-proteins are a diverse family of small regulatory proteins that control function/activity of many proteins/enzymes  They bind GTP and contain an intrinsic GTPase activity (hydrolyze GTP to GDP) that controls its on/off state  In the GTP bound state they are active and can regulate other proteins via direct allosteric interaction  In the GDP bound state they are inactive and cannot interact with target proteins COPII Coated Vesicles and Anterograde Transport COPII coated vesicles: transporting cargo from ER to Golgi complex  Proteins bound for delivery to the Golgi (secreted or processed as soluble or integral membrane proteins of ER, Golgi, lysosomes or peroxisomes) possess an ER export signal in their peptide sequence o Export sequence of transmembrane proteins faces the cytoplasm o For soluble proteins the export sequence is exposed to the lumen of the ER and recognized/bound by specific COPII cargo receptor proteins o COPII vesicle protein coats are composed of 4 structural proteins called sec proteins (named after mutant phenotype in yeast “secretory defective”) o On the cytoplasmic surface of the ER, these sec proteins recognize and bind soluble cargo receptors and ER export signal sequences of TM proteins o The entire process is initiated by a small G-protein called Sar1 o Sar-GTP (active) binds the ER outer membrane and extends an alpha helix into the outer leaflet. This expands the leaflet and initiates curvature o Activated Sar-GTP recruits’ adapter proteins (the sec 23/24 proteins), which find and bind appropriate cargo receptors and TM proteins, aggregating them into a confined space o The recruitment of the Sec proteins continues to curve the ER membrane, rounding it up into a spherical shape o This adapter complex recruits two additional sec proteins that aggregate the cargo and spontaneously assemble as a caged lattice surrounding the membrane vesicle, pinching it free of the ER membrane o Once free, these vesicles must shed these protein coats. This initiated by Sar-mediated hydrolysis of GTP to GDP, causing a conformational change and dissociation of the COPII protein lattice o These vesicles fuse with one another (via the action of the SNARE proteins) into a short lived transition state the ER-Golgi intermediate compartment (ERGIC) o Motor proteins deliver the vesicles to the cis-Golgi network via microtubules where they fuse, again via SNARE dependent process COPI Coated Vesicles: Retrograde Transport  Recycle material from cis-Golgi Network back to ER  Also drive retrograde transport between Golgi cisternae  Proteins re kept in the ER by one of two mechanisms: o Retention of resident molecules excluded form transport vesicles based on physical properties like solubility or association with large protein complexes o Retrieval of “escaped” molecules back to the compartment where they reside Retrieval of ER Proteins: KDEL  Resident ER proteins contain a C-terminal amino acid sequence that functions as a retrieval signal. KDEL (Lys-Asp-Glu-Leu)  Golgi receptors capture such proteins and package them in COPI coated vesicles  Each endomembrane compartment may have its own retrieval signal, but none are as well defined as the ER signal Types of Vesicle Transport and Their Functions  Clathrin coated vesicles perform anterograde movement from trans Golgi Network and also promote endocytosis  Like COPI and COPII vesicles clathrin forms a scaffold around the membrane aided by G-proteins and adapter proteins Lysosomal Proteins as a example of clathrin mediated transport  In the CGN, soluble lysosomal enzymes are identified by specific enzymes that modify the core N-linked glycan through addition of one or more phosphorylated mannose sugars  In the TGN, mannose-6-phosphate receptors bind these modified proteins. The receptor is recognized by adapter proteins that concentrate soluble lysosomal proteins  These adapters then recruit the clathrin proteins that form a scaffold that generates the budding vesicle  Also similar to COPI and COPII vesicles, the clathrin coat must disassemble before the vesicle can be targeted to the lysosomes  Receptor proteins are recycled back to the TGN Sorting and Transport of Non-Lysosomal Proteins  Targeting of secretory proteins to plasma membrane not well understood there is no clear exocytosis peptide or sugar signal  Regulated secretory proteins bud from the TGN and aggregate in dense granules that migrate to plasma membrane and dock in a pre-fusion state  There, the cell awaits a signal that initiates a Ca2+ cytoplasmic influx that promotes vesicle fusion with the membrane  Integral membrane proteins appear to possess diverse peptide signals that direct those proteins to the plasma membrane  Polarized cells segregate apical membrane proteins and lateral/basal membrane proteins at the TGN into separate carriers Targeting and Fusing Vesicles  1. Tethering: Rab-mediated: Rabs are another G protein family; (> 60 in humans) that provide specificity between vesicle and target membrane. motor proteins deliver the vesicles via movement along the microtubule network  Rabs promote 1) physical association between fibrous tethering proteins found on both membranes and 2) transfer to more stable tethering complexes  2) Fusion: between vesicle and target membranes o Proteins that promote fusion are SNAREs (> 35 family members) o Include v-SNAREs (vesicle membrane) and t-SNAREs (target membrane) have complementary domains that promote fusion of the two lipid bilayers  Interactions between v- and t-SNAREs promote vesicle fusion and exocytosis 1. Following rab-mediated tethering and docking to the target membrane complementary v- and t- SNARE proteins associate via -helices 2. Conformational changes through tight electrostatic interactions draw the two membranes close 3. Vesicles remain in this pre-fusion bound state until a release of Ca2+ promotes final membrane fusion  The SNARE proteins are targets of the neurotoxins that cause botulism and tetanus  Both bacterial toxins selectively bind neuronal cells, are endocytosed and cleave either syntaxin or synaptobrevin (the principle complementary SNAREs responsible for neurotransmitter vesicle fusion)  Inhibiting neuronal signaling blocks axonal impulses leading to paralysis Lysosomes  Lysosomes contain diverse acid hydrolases which collectively can digest every type of biological molecule  A low pH required for enzyme activity and is maintained by a proton pump (H+/ATPase) Autophagy  Lysosomes play a key role in organelle turnover  During autophagy, an organelle is surrounded by a double membrane forming an autophaosome  Which ruse with lysosomes allowing compartmentalized digestion  While some material is exocytosed, a large amount is recycled as metabolites for cellular activities  Autophagy evolved as a response to nutrient deprivation The Endocytic Pathway: Moving Membrane and Materials Into the Cell Interior  Endocytosis – uptake of cell surface receptors and bound extracellular ligands  Phagocytosis – uptake of particulate matter  Endocytosis can be divided into two categories: o Pinocytosis – aka bulk phase endocytosis, nonspecific uptake of extracellular fluids that does not involve receptors or clathrin vesicles o Receptor mediated endocytosis – clathrin dependent uptake of specific extracellular ligands following their binding to specific transmembrane receptors  Receptor mediated endocytosis (RME) and the role of clathrin coated pits: o Substances that enter the cell through clathrin mediated RME become bound to coated pits on the plasma membrane o Clathrin coated regions invaginate into the cytoplasm and then pinch free into the cytoplasm o When viewed from the cytoplasm, coated pits appear as polygons resembling a honeycomb o Geometric design is derived from structure of the clathrin building blocks o Clathrin: three heavy and three light chains form a triskelion o Coated vesicles also contain adaptors between clathrin and membrane o Like other transport vesicles, the clathrin coat must shed in order for the vesicle to deliver its contents to the cell interior o Once formed, the clathrin coated pit must be freed form the palsma membrane o Dynamin: a G-protein required for release of clathrin coated vesicles form membrane o Dynamin polymerizes around the neck of the budding vesicle o GTP hydrolysis causes conformation change that twists the neck, pinching it free of the plasma membrane o AP2 adaptors are normally found in cytosol in a locked conformation o Binding of AP2 adapter to PI(4,5)P2 causes a conformational change exposing the cargo binding site, allowing interaction with specific membrane receptors o Distinct phophoinositides are generated by numerous enzymes and dynamically regulate endocytosis: site of vesicle formation, initiation and ability to respond to bound receptor Molecular Organization of a Coated Vesicle  As in the TGN, specific adaptor proteins complex with receptors and their ligands to specify what molecules will be endocytosed  Recruitment of adapter proteins is regulated by the production of modified phosphoinositides – PI(4,5)P2  Adapters also regulate coat disassembly by recruiting specific enzymes The Endocytic Pathway  After internalization, vesicles fuse with other vesicles and tubules forming endosomes: sorting stations  Early endosome found just beneath the plasma membrane surface  Internalized receptors follow one of two fates  Housekeeping receptors: responsible for continuous uptake of material necessary for general activities are recycled back to the membrane for reuse  Low pH dissociates the cargo from the receptors and the cargo maintained in the maturing endosomes  Signaling receptors, bind to extracellular molecules and initiate a cellular response  Such signals are tightly regulated and the cell made insensitive to them once a response is initiated. These receptors are often ubiqutinated following ligand binding  Such receptors are kept within the early endosomes, which fuse and mature into late endosomes (even lower pH)  Within late endosomes these ubiquitinated receptors are processed by enzymes called ESCRT proteins, that internalize small membrane bodies harboring the receptors into the endosome interior]  Late endosomes fuse with lysosomes and their products are degraded and either exocytosed or used as building blocks for metabolic processes – LDL for example provides a supply of lipids and cholesterol LDLs and Cholesterol Metabolism  LDLs are synthesized in the liver and deliver cholesterol to body cells via the blood stream  LDL receptors are concentrated in plasma membrane coated pits, ready for binding LDLs  LDLs taken up by RME and delivered to lysosomes, releasing cholesterol for use by the cells  In the rare recessive disorder Niemann-Pick disease, cholesterol cannot be transported out of the lysosomes leading to neuronal degeneration and early childhood death  Damaged endothelial linings of blood vessels (again, smoking, drinking, elevated radical production) are easily penetrated by LDL forming plaques due to inflammation and immune response. High LDL levels are bad  High density lipoproteins (HDLs) transport cholesterol from tissues to the liver for excretion and are associated with lowering LDL levels. HDL is good Phagocytosis  Uptake of large particles  The plasma membrane takes up a particle and pinches off to form a phagosome  The phagosome fuses with lysosomes and the material is digested within this phagolysosome  Clathrin independent, driven by actin microfilaments extending pseudopods around extracellular material  Forming phagosome that fuse with lysosomes for degradation  Health risk: not all bacteria engulfed by phagocytic cells are destroyed; some hijack phagocytic machinery for their own survival o Mycobacterium tuberculosis (affects fusion with lysosome) o Coxiella burnetti (pH tolerant so can survive in the lysosome) o Listeria monocytogenes (can degrade the lysosome) Posttranslational Uptake of Proteins by Peroxisomes, Mitochondria and Chloroplasts  Integral membrane nuclear proteins are trnalsated on the RER, but proteins of the mitochondria, chloroplast, peroxisomes and soluble nuclear proteins are translated of free ribosomes  Peptide signal sequence serve as addresses for such proteins  Fully folded proteins destined for peroxisomes and the nucleus possess one of several targeting signals (PTS) for translocation into those organelles  However, nuclear encoded mitochondrial and chloroplast protein are fed into these organelles in an unfolded state Uptake of Proteins into Mitochondria  These protein contain a targeting sequence called the pre-sequence  Chaperone proteins bind and maintain mitochondrial bound proteins in unfolded state  Outer mitochondrial membrane TOM complex includes a pre-sequence receptor and channel to move unfolded protein into intermembrane space  Recall the outer mitochondrial membrane is permeable only to small proteins due to porin channel proteins  Distinct innermembrane complexes called TIM complexes direct the nascent protein to either matrix or as integral inner membrane proteins  Matrix destined proteins possess a removable N-terminal pre-sequence cleaved in the matrix before native conformation is established  While IM destined proteins pre-sequence is internal and note removed  In a similar fashion chloroplast targets proteins are imported via the action of homologous TOC and TIC protein compelxes


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