Harpers

Intracellular Traffic & Sortingof Proteins 46Robert K. Murray, MD, PhDBIOMEDICAL IMPORTANCEProteins must travel from polyribosomes to many differentsites in the cell to perform their particular functions.Some are destined to be components of specificorganelles, others for the cytosol or for export, and yetothers will be located in the various cellular membranes.Thus, there is considerable intracellular trafficof proteins. Many studies have shown that the Golgiapparatus plays a major role in the sorting of proteinsfor their correct destinations. A major insight was therecognition that for proteins to attain their proper locations,they generally contain information (a signal orcoding sequence) that targets them appropriately. Oncea number of the signals were defined, it became apparentthat certain diseases result from mutations that affectthese signals. In this chapter we discuss the intracellulartraffic of proteins and their sorting and brieflyconsider some of the disorders that result when abnormalitiesoccur.MANY PROTEINS ARE TARGETEDBY SIGNAL SEQUENCES TO THEIRCORRECT DESTINATIONSThe protein biosynthetic pathways in cells can be consideredto be one large sorting system. Many proteinscarry signals (usually but not always specific sequencesof amino acids) that direct them to their destination,thus ensuring that they will end up in the appropriatemembrane or cell compartment; these signals are a fundamentalcomponent of the sorting system. Usually thesignal sequences are recognized and interact with complementaryareas of proteins that serve as receptors forthe proteins that contain them.A major sorting decision is made early in proteinbiosynthesis, when specific proteins are synthesized eitheron free or on membrane-bound polyribosomes.This results in two sorting branches called the cytosolicbranch and the rough endoplasmic reticulum (RER)branch (Figure 46–1). This sorting occurs because proteinssynthesized on membrane-bound polyribosomescontain a signal peptide that mediates their attachmentto the membrane of the ER. Further details on498the signal peptide are given below. Proteins synthesizedon free polyribosomes lack this particular signal peptideand are delivered into the cytosol. There they aredirected to mitochondria, nuclei, and peroxisomes byspecific signals—or remain in the cytosol if they lack asignal. Any protein that contains a targeting sequencethat is subsequently removed is designated as a preprotein.In some cases a second peptide is also removed,and in that event the original protein is known as a preproprotein(eg, preproalbumin; Chapter 50).Proteins synthesized and sorted in the rough ERbranch (Figure 46–2) include many destined for variousmembranes (eg, of the ER, Golgi apparatus, lysosomes,and plasma membrane) and for secretion. Lysosomalenzymes are also included. Thus, such proteinsmay reside in the membranes or lumens of the ER orfollow the major transport route of intracellular proteinsto the Golgi apparatus. Further signal-mediatedsorting of certain proteins occurs in the Golgi apparatus,resulting in delivery to lysosomes, membranes ofthe Golgi apparatus, and other sites. Proteins destinedfor the plasma membrane or for secretion pass throughthe Golgi apparatus but generally are not thought tocarry specific sorting signals; they are believed to reachtheir destinations by default.The entire pathway of ER → Golgi apparatus →plasma membrane is often called the secretory or exocytoticpathway. Events along this route will be givenspecial attention. Most of the proteins reaching theGolgi apparatus or the plasma membrane are carried intransport vesicles; a brief description of the formationof these important particles will be given subsequently.Other proteins destined for secretion are carried in secretoryvesicles (Figure 46–2). These are prominent inthe pancreas and certain other glands. Their mobilizationand discharge are regulated and often referred to as“regulated secretion,” whereas the secretory pathwayinvolving transport vesicles is called “constitutive.”Experimental approaches that have afforded majorinsights to the processes described in this chapter include(1) use of yeast mutants; (2) application of recombinantDNA techniques (eg, mutating or eliminatingparticular sequences in proteins, or fusing newsequences onto them; and (3) development of in vitro