Class Note for BME 510 at UA 2
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Date Created: 02/06/15
BME 510 Lynch October 29 2008 The Endosomal Pathway and Receptor Recycling see Lodish CH 14 The endocytic pathway plays many roles in normal cell function The retrieval of membrane from the cell surface along with speci c integral membrane proteins is required for processing of signals from the cell environment The pathway also is used to cycle rapidly proteins back to the surface including secretory proteins in neurons A macrophage turns over its entire membrane surface area in about 1 hour Most cells endocytose at somewhat slower rates but the turnover of the membrane and many of its components remains quite rapid in most if not all cells The endocytic pathway removes membrane from the cell surface and incorporates it into intracellular membrane compartments the nature of which are not completely understood Hopkins 1990 During the process of membrane retrieval speci c proteins in the membrane are intemalized and substances outside the cell near its surface maybe in association with a receptor can be internalized phagocytosis or pinocytosis The contents of the vesicle can be moved to lysosomal compartment where acid hydrolases degrade most nonlipids including modi cation of proteins such as receptors that can be cycled back to the plasma membrane In epithelial cells movement from one surface to the other is called transcytosis and is likely to occur within the same compartments with signals that direct the contents to either the apical or basolateial membranes Finally in neurons secretory vesicles are recycled at the synapse to alleviate the need for rapid and continuous replacement of vesicles which required transport from the cell body along the axon to the synapse Figure Smooth Muscle Cell incubated with a reddextran for 6 hours then labeled with a golgi speci c probe green Deconvolution microscopy was used to acquire this image Endosomes Lysosomes are loaded with the dextran by pinocytosis N nucleus ReceptarmediatedEndacytasix When transmembrane receptor molecules are occupied with their agonists they accumulate into surface invaginations which are coated with clathrin This provides a mechanism for concentrating both receptors and their ligands prior to incorporation into the cell Clathrin acts in organizing the submembrane structure required for vesicle formation but is quickly lost after the invaginated membrane is engulfed into the cell Most membrane localized proteins are not incorporated into clathrin coated pits again indicating that this mechanism is associated with molecular sorting steps normally associated with targeting sequences To date all receptor proteins found to localize to clathrin pits lose this ability if W specific intra cellular regions are modi ed Lomw39pmr Dmuvm Diagram The mechanism used to incorporate coated an L 7 n cholesterol into cells using the surface LDL low mm 5 5 mm W density lipoprotein receptor The LDLreceptor is a glyco protein composed of 840 amino acids of which only 50 residues reside in the cytoplasm If the cytoplasmic domain is deleted the LDL receptor continues to bind LDL but the complex Wm cannotbe endocytosed LDLreceuwrpmlemwur membrane defective COMM m binding me LDL llmdlll six LDL g dathnn and other coaraesmxzred prurems CYTDPLASM BME 510 Lynch October 29 2008 Once the LDL with its receptor is internalized the clathrin coat is lost and the new vesicle begins to acidify due to insertion ofthe V type Hl ATPase Acidi cation appears to be required for separation ofligand from its receptor Generally a receptor is returned to the membrane while the ligand is further processes potentially at the level of the lysosome For LDL and cholesterol assimilation the mechanism by which this process is regulated is primarily at the level ofLDL receptor translation Ifmore cholesterol is required more receptor is transcribed and inserted into the membrane via the constitutive pathway then recycled via endocytosis There are at least 40 known receptors which are internalized using this form oftargeting mechanism Not only do the receptors and their ligands become internalized during this process but so too does uid near the membrane By placing factors in the media the uid phase ofthe endosomallysosomal pathway can be specifically loaded and differences in the movement of uid and membrane localized proteins can be followed which is the focus ofthe discussion paper by Hopkins et al 1990 Hopkins CR et al 1990 Movement of internalized ligandreceptor complexes along a continuous endosomal reticulum Nature 346 335339 Regulation of pH in Intracellular Compartments The regulation of pH within subcellular compartments is crucial for maintaining macromolecular trafficking from one intracellular compartment to another In the endocytic pathway receptor bound ligands and dissolved substances in the extracellular uid are taken up at the plasma membrane by specialized structures that form early endosomes The endosomal lumen rapidly acidifies inducing the dissociation of endocytosed receptor ligand complexes The endosomal contents may be recycled back to the plasma membrane as in the transferrin system or undergo further degradation in late endosomes and lysosomes In the regulated exocytic pathway of hormone secreting cells the acidic environment of the secretory vesicle regulates the proteolytic processing of prohormones into the mature form of the secreted peptide For example in the pancreatic beta cell the cleavage of the proinsulin B chain and C chain by a specific endopeptidase requires an acidic environment within the secretory granule Conversely it has been suggested that alkalinization of the secretory granule lumen upon activation of secretion should occur to promote solubility of the stored and condensed insulin to enhance its release from the granule upon fusion with the plasma membrane Sorting to the Lvsosomal Compartments Sorting of acid hydrolases from the Golgi to lysosomes has been described in some detail Acid hydrolases are glycosylated in the ERGolgi then in the trans golgi Mannose 6 Phosphate M 6 P groups are added Only peptides with M 6 P markers are incorporated into vesicles destined to be lysosomes and this is directed by a receptor protein for the M 6 P As indicated by their names these hydrolases are most active under acidic conditions pHlt5 Since the vesicular pH is thought to be near 7 initially a maturation process where pH decreases must take place A H ATPase V type is responsible for the acidification but this protein is not tagged by M 6 P Therefore the V type ATPase may come from an endocytic route and elicit acidification only after endocytic substances become incorporated The acid hydrolyses remain membrane attached via the receptor until acidification occurs then the receptors are cycled back to the golgi Thus it appears that all intacellular compartments can be in contact with the exception of mitochondria A current argument proposes vesicles observed by microscopy are actually part ofa continuous cellular membrane compartment through which substances travel in speci c directions due to intra molecular signals
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