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Alberts B, Bray D, Lewis J, et al. Molecular Biology of the Cell. 3rd edition. New York: Garland Science; 1994.

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Molecular Biology of the Cell. 3rd edition.

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The Compartmentalization of Higher Cells

Introduction

In this introductory section we give a brief overview of the compartments of the cell and of the relationships between them. In doing so, we organize the organelles conceptually into a small number of discrete families, discussing how proteins are directed to specific organelles and how they cross organelle membranes.

All Eucaryotic Cells Have the Same Basic Set of Membrane-bounded Organelles 1

Many vital biochemical processes take place in or on membrane surfaces. Lipid metabolism, for example, is catalyzed mostly by membrane-bound enzymes, and oxidative phosphorylation and photosynthesis both require a membrane in order to couple the transport of H + to the synthesis of ATP. Intracellular membrane systems, however, do more for the cell than just provide increased membrane area: they create enclosed compartments that are separate from the cytosol, thus providing the cell with functionally specialized aqueous spaces. Because the lipid bilayer of organelle membranes is impermeable to most hydrophilic molecules, the membrane of each organelle must contain transport proteins that are responsible for the import and export of specific metabolites. Each organelle membrane must also have a mechanism for importing, and incorporating into the organelle, the specific proteins that make the organelle unique.

The major intracellular compartments common to eucaryotic cells are illustrated in Figure 12-1. The nucleus contains the main genome and is the principal site of DNA and RNA synthesis. The surrounding cytoplasm consists of the cytosol and the cytoplasmic organelles suspended in it. The cytosol constitutes a little more than half the total volume of the cell and is the site of protein synthesis and of most of the cell's intermediary metabolism - that is, the many reactions by which some small molecules are degraded and others are synthesized to provide the building blocks of macromolecules (discussed in Chapter 2).

Figure 12-1. The major intracellular compartments of an animal cell.

Figure 12-1

The major intracellular compartments of an animal cell. The cytosol ( gray), endoplasmic reticulum, Golgi apparatus, nucleus, mitochondrion, endosome, lysosome, and peroxisome are distinct compartments isolated from the rest of the cell by at least one selectively (more...)

About half the total area of membrane in a cell encloses the labyrinthine spaces of the endoplasmic reticulum (ER). The ER has many ribosomes bound to its cytosolic surface; these are engaged in the synthesis of integral membrane proteins and soluble proteins, most of which are destined for secretion or for other organelles. We shall see that this reflects an important difference between how proteins are directed to the ER and how they are directed to other cytoplasmic organelles: whereas proteins are translocated into other organelles only after their synthesis is complete, they are translocated into the ER during their synthesis, and hence the ribosomes on which they are made are tethered to the ER membrane. The ER also produces the lipid for the rest of the cell and functions as a store for Ca 2+ ions. The Golgi apparatus consists of organized stacks of disclike compartments called Golgi cisternae; it receives lipids and proteins from the ER and dispatches them to a variety of destinations, usually covalently modifying them en route .

Mitochondria and (in plants) chloroplasts generate most of the ATP used to drive cellular reactions that require an input of free energy. Lysosomes contain digestive enzymes that degrade defunct intracellular organelles, as well as macromolecules and particles taken in from outside the cell by endocytosis. On their way to lysosomes, endocytosed material must first pass through a series of compartments called endosomes. Peroxisomes (also known as microbodies) are small vesicular compartments that contain enzymes utilized in a variety of oxidative reactions. In general, each membrane-bounded organelle carries out the same set of basic functions in all cell types but varies in abundance and can have additional properties that differ from cell type to cell type according to the specialized functions of differentiated cells.

On average, the membrane-bounded compartments together occupy nearly half the volume of a cell ( Table 12-1), and a large amount of intracellular membrane is required to make them all. In the two mammalian cells analyzed in Table 12-2, for example, the endoplasmic reticulum has a total membrane surface area that is, respectively, 25 times and 12 times that of the plasma membrane. In terms of its area and mass the plasma membrane is only a minor membrane in most eucaryotic cells ( Figure 12-2).

Table 12-1. The Relative Volumes Occupied by the Major Intracellular Compartments in a Liver Cell (Hepatocyte).

Table 12-1

The Relative Volumes Occupied by the Major Intracellular Compartments in a Liver Cell (Hepatocyte).

Table
12-2. Relative Amounts of Membrane Types in Two Types of Eucaryotic Cells.

Table 12-2

Relative Amounts of Membrane Types in Two Types of Eucaryotic Cells.

Figure 12-2. Electron micrograph of part of a liver cell seen in cross-section.

Figure 12-2

Electron micrograph of part of a liver cell seen in cross-section. Examples of most of the major intracellular compartments are indicated. (Courtesy of Daniel S. Friend.)

Membrane-bounded organelles are not randomly distributed in the cytosol; instead they often have characteristic positions. In most cells, for example, the Golgi apparatus is located close to the nucleus, whereas the network of ER tubules extends from the nucleus throughout the entire cytosol. These characteristic distributions seem to depend on interactions of the organelles with the cytoskeleton: the localization of both the ER and the Golgi apparatus, for example, is dependent on an intact microtubule array; if the microtubules are experimentally depolymerized with a drug, the Golgi apparatus fragments and disperses throughout the cell and the ER network collapses toward the cell center, or centrosome, from which the microtubule array emanates (discussed in Chapter 16).

The Topological Relationships of Membrane-bounded Organelles Can Be Interpreted in Terms of Their Evolutionary Origins 2

To understand the relationships between the compartments of the cell, it is helpful to consider how they might have evolved. The precursors of the first eucaryotic cells are thought to have been simple organisms that resembled bacteria, which generally have a plasma membrane but no internal membranes. The plasma membrane in such cells therefore provides all membrane-dependent functions, including the pumping of ions, ATP synthesis, protein secretion, and lipid synthesis. Typical present-day eucaryotic cells are 10 to 30 times larger in linear dimension and 1000 to 10,000 times greater in volume than a typical bacterium such as E. coli. The profusion of internal membranes can be seen in part as an adaptation to this increase in size: the eucaryotic cell has a much smaller ratio of surface to volume, and its area of plasma membrane is presumably too small to sustain the many vital functions for which membranes are required.

The evolution of internal membranes evidently has gone hand in hand with specialization of membrane function. Some present-day bacteria have specialized patches of plasma membrane in which a selected set of membrane proteins coalesce to carry out a group of related functions ( Figure 12-3A). These specialized membrane patches, such as the "purple membrane" containing bacterio-rhodopsin in Halobacterium (discussed in Chapter 10) and the chromatophores in photosynthetic bacteria (discussed in Chapter 14), represent primitive organelles. In some photosynthetic bacteria the patches have become elaborated into extensive invaginations of the plasma membrane ( Figure 12-3B); in others the invaginations seem to have pinched off completely, forming sealed membrane-bounded vesicles specialized for photosynthesis ( Figure 12-3C).

Figure 12-3. Organization of specialized membranes in bacteria.

Figure 12-3

Organization of specialized membranes in bacteria. (A) Membrane patches on the cell surface consisting of clusters of specialized membrane proteins. (B) Invaginated patches of plasma membrane that increase the amount of membrane available for a specialized (more...)

A eucaryotic organelle that originated by the type of pathway illustrated in Figure 12-3 might be expected to have an interior that is topologically equivalent to the exterior of the cell. We shall see that this is the case for the ER, Golgi apparatus, endosome, and lysosome - as well as for the many vesicular intermediates ( transport vesicles) in the secretory and endocytic pathways. We can therefore think of all of these organelles as members of the same family, and, as we discuss in detail in the next chapter, their interiors communicate extensively with one another and with the outside of the cell via transport vesicles that bud off from one organelle and fuse with another ( Figure 12-4). Ribosomes are found attached to the cytosolic side of the plasma membrane in bacteria, and so the evolutionary origin of the ER membrane from the plasma membrane may explain why ribosomes are attached to the ER membrane in eucaryotic cells.

Figure 12-4. Topological relationships between compartments in a eucaryotic cell.

Figure 12-4

Topological relationships between compartments in a eucaryotic cell. Topologically equivalent spaces are shown in red. In principle, cycles of vesicle budding and fusion permit any lumen to communicate with any other and with the cell exterior. The blue (more...)

This evolutionary scheme also offers a reasonable explanation for the architecture of the cell nucleus with its double membrane. In bacteria the single chromosome is attached at special sites to the inside of the plasma membrane. It is possible therefore that the double-layered nuclear envelope originated as a deep invagination of the plasma membrane, as shown in Figure 12-5A. This scheme would explain why the nuclear compartment is topologically equivalent to the cytosol. In fact, in higher eucaryotic cells the nuclear envelope breaks down during mitosis, allowing the nuclear contents to disperse in the cytosol, a situation that never occurs for the contents of any other membrane-bounded organelle. As the scheme in Figure 12-5A also predicts, the space between the two nuclear membranes is topologically equivalent to the exterior of the cell and is continuous with the lumen of the ER.

Figure 12-5. Hypotheses for the evolutionary origins of some membrane-bounded organelles.

Figure 12-5

Hypotheses for the evolutionary origins of some membrane-bounded organelles. The origins of mitochondria, chloroplasts, ER, and the cell nucleus could explain the topological relationships of these intracellular compartments in eucaryotic cells. (A) A (more...)

As discussed in Chapter 14, mitochondria and plastids (of which chloroplasts are one form) differ from the other membrane-bounded organelles in that they contain their own genomes. The nature of these genomes and the close resemblance of the proteins in these organelles to those in some present-day bacteria strongly suggest that mitochondria and plastids evolved from bacteria that were engulfed by other cells with which they initially lived in symbiosis (discussed in Chapters 1 and 14). According to the hypothetical scheme shown in Figure 12-5B, the inner membrane of mitochondria and plastids corresponds to the original plasma membrane of the bacterium, while the lumen of these organelles evolved from the bacterial cytosol. As might be expected from such origins, these two organelles remain isolated from the extensive vesicular traffic that connects the interiors of most of the other membrane-bounded organelles to one another and to the outside of the cell.

This evolutionary scheme groups the intracellular compartments in eucaryotic cells into five distinct families: (1) the nucleus and the cytosol, which communicate through the nuclear pores and are thus topologically continuous (although functionally distinct); (2) all organelles that function in the secretory and endocytic pathways - including the ER, Golgi apparatus, endosomes, lysosomes, and numerous classes of transport vesicles; (3) the mitochondria; (4) the plastids (in plants only); and (5) the peroxisomes (whose evolutionary origins are discussed later).

Proteins Can Move Between Compartments in Different Ways 3

All proteins begin being synthesized on ribosomes in the cytosol, except for the few that are synthesized on the ribosomes of mitochondria and plastids. Their subsequent fate depends on their amino acid sequence, which can contain sorting signals that direct their delivery to locations outside the cytosol. Most proteins do not have a sorting signal and consequently remain in the cytosol as permanent residents. Many others, however, have specific sorting signals that direct their transport from the cytosol into the nucleus, the ER, mitochondria, plastids (in plants), or peroxisomes; sorting signals can also direct the transport of proteins from the ER to other destinations in the cell.

To understand the general principles by which sorting signals operate, it is important to distinguish three fundamentally different ways by which proteins move from one compartment to another. (1) The protein traffic between the cytosol and nucleus occurs between topologically equivalent spaces, which are in continuity through the nuclear pore complexes. This process is called gated transport because the nuclear pore complexes function as selective gates that can actively transport specific macromolecules and macromolecular assemblies, although they also allow free diffusion of smaller molecules. (2) In transmembrane transport membrane-bound protein translocatorsdirectly transport specific proteins across a membrane from the cytosol into a space that is topologically distinct. The transported protein molecule usually must unfold in order to snake through the membrane. The initial transport of selected proteins from the cytosol into the ER lumen or into mitochondria, for example, occurs in this way. (3) In vesicular transport, transport vesicles ferry proteins from one compartment to another. The vesicles become loaded with a cargo of molecules derived from the lumen of one compartment as they pinch off from its membrane; they discharge their cargo into a second compartment by fusing with its membrane. The transfer of soluble proteins from the ER to the Golgi apparatus, for example, occurs in this way. Because the transported proteins do not cross a membrane, they move only between compartments that are topologically equivalent ( Figure 12-6). We discuss vesicular transport in more detail in Chapter 13. The three ways in which proteins are transported between different compartments are summarized in Figure 12-7.

Figure 12-6. The "sidedness" of membranes is preserved during vesicular transport.

Figure 12-6

The "sidedness" of membranes is preserved during vesicular transport. Note that the original orientation of both proteins and lipids in the donor-compartment membrane is preserved in the target-compartment membrane and that soluble molecules are transferred from (more...)

Figure 12-7. A simplified "road map" of protein traffic.

Figure 12-7

A simplified "road map" of protein traffic. Proteins can move from one compartment to another by gated transport ( red), trans-membrane transport ( blue), or vesicular transport ( green). The signals that direct a given protein's movement through the (more...)

Each of the three modes of protein transfer is usually selectively guided by sorting signals in the transported protein that are recognized by complementary receptor proteins in the target organelle. If a large protein is to be imported into the nucleus, for example, it must possess a sorting signal that is recognized by receptor proteins associated with the nuclear pore complex. If a protein is to be transferred directly across a membrane, it must possess a sorting signal that is recognized by the translocator in the membrane to be crossed. Likewise, if a protein is to be incorporated into certain types of transport vesicles or to be retained in certain organelles, its sorting signal must be recognized by a complementary receptor in the appropriate membrane.

Signal Peptides and Signal Patches Direct Proteins to the Correct Cellular Address 4

There are at least two types of sorting signals on proteins. One type resides in a continuous stretch of amino acid sequence, typically 15 to 60 residues long. This signal peptide is often (but not always) removed from the finished protein by a specialized signal peptidase once the sorting process has been completed. The other type consists of a specific three-dimensional arrangement of atoms on the protein's surface that forms when the protein folds up. The amino acid residues that comprise this signal patch can be distant from one another in the linear amino acid sequence, and they generally remain in the finished protein ( Figure 12-8). Signal peptides are used to direct proteins from the cytosol into the ER, mitochondria, chloroplasts, peroxisomes, and nucleus, and they are also used to retain soluble proteins in the ER. Signal patches identify certain enzymes that are to be marked with specific sugar residues that then direct them from the Golgi apparatus into lysosomes; signal patches are also used in other sorting steps that have been less well characterized.

Figure 12-8. Two ways that a sorting signal can be built into a protein.

Figure 12-8

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 (more...)

Different types of signal peptides are used to specify different destinations in the cell. Proteins destined for initial transfer to the ER usually have a signal peptide at their amino terminus, which characteristically includes a sequence composed of about 5 to 10 hydrophobic amino acids. Most of these proteins will in turn pass from the ER to the Golgi apparatus, but those with a specific sequence of four amino acids at their carboxyl terminus are retained as permanent ER residents. Proteins destined for mitochondria have signal peptides of yet another type, in which positively charged amino acids alternate with hydrophobic ones. Proteins destined for peroxisomes usually have a specific signal sequence of three amino acids at their carboxyl terminus. Many proteins destined for the nucleus carry a signal peptide formed from a cluster of positively charged amino acids, which is commonly found at internal sites of the polypeptide chain. Some typical signal peptides are listed in Table 12-3.

Table 12-3. Some Typical Signal Peptides.

Table 12-3

Some Typical Signal Peptides.

The importance of each of these signal peptides for protein targeting has been shown by experiments in which the peptide is transferred from one protein to another by genetic engineering techniques: placing the amino-terminal ER signal peptide at the beginning of a cytosolic protein, for example, redirects the protein to the ER. Even though their amino acid sequences can vary greatly, the signal peptides of all proteins having the same destination are functionally interchangeable: physical properties, such as hydrophobicity, often appear to be more important in the signal-recognition process than the exact amino acid sequence.

Signal patches are far more difficult to analyze than signal peptides, and so less is known about their structure. Because they result from a complex three-dimensional protein-folding pattern, they cannot be easily transferred experimentally from one protein to another.

The main ways of studying how proteins are directed from the cytosol to a specific compartment and how they are translocated across membranes are illustrated in Panel 12-1 (pp. 559).

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Panel 12-1

Approaches to studying signal sequences and protein translocation across membranes.

Cells Cannot Construct Their Membrane-bounded Organelles de Novo: They Require Information in the Organelle Itself 5

When a cell reproduces by division, it has to duplicate its membrane-bounded organelles. In general, cells do this by enlarging the existing organelles by incorporating new molecules into them; the enlarged organelles then divide and are distributed to the two daughter cells. Thus each daughter cell inherits from its mother a complete set of specialized cell membranes. This inheritance is essential because a cell could not make such membranes de novo. If the ER were completely removed from a cell, for example, how could the cell reconstruct it? The membrane proteins that define the ER and carry out many of its functions are themselves products of the ER. A new ER could not be made without an existing ER or, at the very least, a membrane that contains the translocators required to import specific proteins into the ER (and lacks the translocators required to import the proteins that function in other organelles).

Thus it seems that the information required to construct a membrane-bounded organelle does not reside exclusively in the DNA that specifies the organelle's proteins. Epigeneticinformation in the form of at least one distinct protein that preexists in the organelle membrane is also required, and this information is passed from parent cell to progeny cell in the form of the organelle itself. Presumably, such information is essential for the propagation of the cell's compartmental organization, just as the information in DNA is essential for the propagation of its nucleotide and amino acid sequences.

Summary

Eucaryotic cells contain intracellular membranes that enclose nearly half the cell's total volume in separate intracellular compartments called organelles. The main types of membrane-bounded organelles that are present in all eucaryotic cells are the endoplasmic reticulum, Golgi apparatus, nucleus, mitochondria, lysosomes, endosomes, and peroxisomes; plant cells also contain plastids, such as chloroplasts. Each organelle contains a distinct set of proteins that mediates its unique functions.

Each newly synthesized organelle protein finds its way from the ribosome where it is made to the organelle where it functions by following a specific pathway, guided by signals in its amino acid sequence that function as signal peptides or signal patches. The signal peptides and patches are recognized by complementary receptor proteins in the target organelle. Proteins that function in the cytosol do not contain signal peptides or signal patches and therefore remain in the cytosol after they are synthesized.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D Watson.
Bookshelf ID: NBK28395