Harpers

INTRACELLULAR TRAFFIC & SORTING OF PROTEINS / 507This sequence specifies that such proteins will be attachedto the inner aspect of the ER in a relatively loosemanner. The chaperone BiP (see below) is one suchprotein. Actually, KDEL-containing proteins first travelto the Golgi, interact there with a specific KDEL receptorprotein, and then return in transport vesicles to theER, where they dissociate from the receptor.D. RETROGRADE TRANSPORT FROMTHE GOLGI APPARATUSCertain other non-KDEL-containing proteins destinedfor the membranes of the ER also pass to the Golgi andthen return, by retrograde vesicular transport, to the ERto be inserted therein (see below).The foregoing paragraphs demonstrate that a varietyof routes are involved in assembly of the proteins ofthe ER membranes; a similar situation probably holdsfor other membranes (eg, the mitochondrial membranesand the plasma membrane). Precise targeting sequenceshave been identified in some instances (eg,KDEL sequences).The topic of membrane biogenesis is discussed furtherlater in this chapter.PROTEINS MOVE THROUGH CELLULARCOMPARTMENTS TO SPECIFICDESTINATIONSA scheme representing the possible flow of proteinsalong the ER → Golgi apparatus → plasma membraneroute is shown in Figure 46–6. The horizontal arrowsdenote transport steps that may be independent of targetingsignals, whereas the vertical open arrows representsteps that depend on specific signals. Thus, flow ofcertain proteins (including membrane proteins) fromthe ER to the plasma membrane (designated “bulkflow,” as it is nonselective) probably occurs without anytargeting sequences being involved, ie, by default. Onthe other hand, insertion of resident proteins into theER and Golgi membranes is dependent upon specificsignals (eg, KDEL or halt-transfer sequences for theER). Similarly, transport of many enzymes to lysosomesis dependent upon the Man 6-P signal (Chapter 47),and a signal may be involved for entry of proteins intosecretory granules. Table 46–4 summarizes informationon sequences that are known to be involved in targetingvarious proteins to their correct intracellular sites.CHAPERONES ARE PROTEINSTHAT PREVENT FAULTY FOLDING& UNPRODUCTIVE INTERACTIONSOF OTHER PROTEINSExit from the ER may be the rate-limiting step in thesecretory pathway. In this context, it has been foundthat certain proteins play a role in the assembly orproper folding of other proteins without themselvesbeing components of the latter. Such proteins are calledmolecular chaperones; a number of important propertiesof these proteins are listed in Table 46–5, and thenames of some of particular importance in the ER arelisted in Table 46–6. Basically, they stabilize unfoldedLysosomesERcisGolgimedialGolgitransGolgiCellsurfaceSecretorystorage vesiclesFigure 46–6. Flow of membrane proteins from the endoplasmicreticulum (ER) to the cell surface. Horizontal arrows denotesteps that have been proposed to be signal independent andthus represent bulk flow. The open vertical arrows in the boxesdenote retention of proteins that are resident in the membranesof the organelle indicated. The open vertical arrows outside theboxes indicate signal-mediated transport to lysosomes and secretorystorage granules. (Reproduced, with permission, from PfefferSR, Rothman JE: Biosynthetic protein transport and sorting by the endoplasmicreticulum and Golgi. Annu Rev Biochem 1987;56:829.)