The Mitochondrion Both Imports Synthesizes Proteins

Mitochondria contain many proteins. Thirteen proteins (mostly membrane components of the electron transport chain) are encoded by the mitochondrial genome and synthesized in that organelle using its own protein-synthesizing system. However, the majority (at least several hundred) are encoded by nuclear genes, are synthesized outside the mitochondria on cytosolic polyribosomes, and must be imported. Yeast cells have proved to be a particularly useful system for analyzing the mechanisms of import of mitochondrial proteins, partly because it has proved possible to generate a variety of mutants that have illuminated the fundamental processes involved. Most progress has been made in the study of proteins present in the mitochondrial matrix, such as the Fj ATPase subunits. Only the pathway of import of matrix proteins will be discussed in any detail here.

Matrix proteins must pass from cytosolic polyribo-somes through the outer and inner mitochondrial membranes to reach their destination. Passage through the two membranes is called translocation. They have an amino terminal leader sequence (presequence), about 20-80 amino acids in length, which is not highly conserved but contains many positively charged amino acids (eg, Lys or Arg). The presequence is equivalent to a signal peptide mediating attachment of polyribosomes to membranes of the ER (see below), but in this instance targeting proteins to the matrix; if the leader sequence is cleaved off, potential matrix proteins will not reach their destination.

Translocation is believed to occur posttranslation-ally, after the matrix proteins are released from the cy-tosolic polyribosomes. Interactions with a number of cytosolic proteins that act as chaperones (see below) and as targeting factors occur prior to translocation.

Two distinct translocation complexes are situated in the outer and inner mitochondrial membranes, referred to (respectively) as TOM (translocase-of-the-outer membrane) and TIM (translocase-of-the-inner membrane). Each complex has been analyzed and found to be composed of a number of proteins, some of which act as receptors for the incoming proteins and others as components of the transmembrane pores through which these proteins must pass. Proteins must be in the unfolded state to pass through the complexes, and this is made possible by ATP-dependent binding to several chaperone proteins. The roles of chaperone proteins in protein folding are discussed later in this chapter. In mitochondria, they are involved in translocation, sorting, folding, assembly, and degradation of imported proteins. A proton-motive force across the inner membrane is required for import; it is made up of the electric potential across the membrane (inside negative) and the pH gradient (see Chapter 12). The positively charged leader sequence may be helped through the membrane by the negative charge in the matrix. The presequence is split off in the matrix by a matrix-processing peptidase (MPP). Contact with other chaperones present in the matrix is essential to complete the overall process of import. Interaction with mt-Hsp70 (Hsp = heat shock protein) ensures proper import into the matrix and prevents misfolding or aggregation, while interaction with the mt-Hsp60-Hsp10 system ensures proper folding. The latter proteins resemble the bacterial GroEL chaperonins, a subclass of chaperones that form complex cage-like assemblies made up of heptameric ring structures. The interactions of imported proteins with the above chap-erones require hydrolysis of ATP to drive them.

The details of how preproteins are translocated have not been fully elucidated. It is possible that the electric potential associated with the inner mitochondrial membrane causes a conformational change in the unfolded preprotein being translocated and that this helps to pull it across. Furthermore, the fact that the matrix is more negative than the intermembrane space may "attract" the positively charged amino terminal of the preprotein

(1) Cytosolic

Polyribosomes

Secretory storage granule

Secretory storage granule

Endoplasmic reticulum

Nuclear envelope

Endoplasmic reticulum

Nuclear envelope

Figure 46-2. Diagrammatic representation of the rough endoplasmic reticulum branch of protein sorting. Newly synthesized proteins are inserted into the ER membrane or lumen from membrane-bound polyribosomes (small black circles studding the cytosolic face of the ER). Those proteins that are transported out of the ER (indicated by solid black arrows) do so from ribosome-free transitional elements. Such proteins may then pass through the various subcompart-ments of the Golgi until they reach the TGN, the exit side of the Golgi. In the TGN, proteins are segregated and sorted. Secretory proteins accumulate in secretory storage granules from which they may be expelled as shown in the upper right-hand side of the figure. Proteins destined for the plasma membrane or those that are secreted in a constitutive manner are carried out to the cell surface in transport vesicles, as indicated in the upper middle area of the figure. Some proteins may reach the cell surface via late and early endosomes. Other proteins enter prelysosomes (late endosomes) and are selectively transferred to lysosomes. The endocytic pathway illustrated in the upper left-hand area of the figure is considered elsewhere in this chapter. Retrieval from the Golgi apparatus to the ER is not considered in this scheme. (CGN, c/'s-Golgi network; TGN, trans-Golgi network.) (Courtesy of E Degen.) jqq to enter the matrix. Close contact between the membrane sites in the outer and inner membranes involved in translocation is necessary.

The above describes the major pathway of proteins destined for the mitochondrial matrix. However, certain proteins insert into the outer mitochondrial membrane facilitated by the TOM complex. Others stop in the intermembrane space, and some insert into the inner membrane. Yet others proceed into the matrix and then return to the inner membrane or intermembrane space. A number of proteins contain two signaling sequences—one to enter the mitochondrial matrix and the other to mediate subsequent relocation (eg, into the inner membrane). Certain mitochondrial proteins do not contain presequences (eg, cytochrome c, which locates in the inter membrane space), and others contain internal presequences. Overall, proteins employ a variety of mechanisms and routes to attain their final destinations in mitochondria.

General features that apply to the import of proteins into organelles, including mitochondria and some of the other organelles to be discussed below, are summarized in Table 46-1.

IMPORTINS & EXPORTINS ARE INVOLVED IN TRANSPORT OF MACROMOLECULES IN & OUT OF THE NUCLEUS

It has been estimated that more than a million macro-molecules per minute are transported between the nucleus and the cytoplasm in an active eukaryotic cell.

Table 46-1. Some general features of protein import to organelles.1

• Import of a protein into an organelle usually occurs in three stages: recognition, translocation, and maturation.

• Targeting sequences on the protein are recognized in the cytoplasm or on the surface of the organelle.

• The protein is unfolded for translocation, a state maintained in the cytoplasm by chaperones.

• Threading of the protein through a membrane requires energy and organellar chaperones on the trans side of the membrane.

• Cycles of binding and release of the protein to the chaper-one result in pulling of its polypeptide chain through the membrane.

• Other proteins within the organelle catalyze folding of the protein, often attaching cofactors or oligosaccharides and assembling them into active monomers or oligomers.

1Data from McNew JA, Goodman JM: The targeting and assembly of peroxisomal proteins: some old rules do not apply. Trends

Biochem Sci 1998;21:54.

These macromolecules include histones, ribosomal proteins and ribosomal subunits, transcription factors, and mRNA molecules. The transport is bidirectional and occurs through the nuclear pore complexes (NPCs). These are complex structures with a mass approximately 30 times that of a ribosome and are composed of about 100 different proteins. The diameter of an NPC is approximately 9 nm but can increase up to approximately 28 nm. Molecules smaller than about 40 kDa can pass through the channel of the NPC by diffusion, but special translocation mechanisms exist for larger molecules. These mechanisms are under intensive investigation, but some important features have already emerged.

Here we shall mainly describe nuclear import of certain macromolecules. The general picture that has emerged is that proteins to be imported (cargo molecules) carry a nuclear localization signal (NLS). One example of an NLS is the amino acid sequence (Pro)2-(Lys)4-Ala-Lys-Val, which is markedly rich in basic lysine residues. Depending on which NLS it contains, a cargo molecule interacts with one of a family of soluble proteins called importins, and the complex docks at the NPC. Another family of proteins called Ran plays a critical regulatory role in the interaction of the complex with the NPC and in its translocation through the NPC. Ran proteins are small monomeric nuclear GTP-ases and, like other GTPases, exist in either GTP-bound or GDP-bound states. They are themselves regulated by guanine nucleotide exchange factors (GEFs; eg, the protein RCC1 in eukaryotes), which are located in the nucleus, and Ran guanine-activating proteins (GAPs), which are predominantly cytoplas-mic. The GTP-bound state of Ran is favored in the nucleus and the GDP-bound state in the cytoplasm. The conformations and activities of Ran molecules vary depending on whether GTP or GDP is bound to them (the GTP-bound state is active; see discussion of G proteins in Chapter 43). The asymmetry between nucleus and cytoplasm—with respect to which of these two nucleotides is bound to Ran molecules—is thought to be crucial in understanding the roles of Ran in transferring complexes unidirectionally across the NPC. When cargo molecules are released inside the nucleus, the im-portins recirculate to the cytoplasm to be used again. Figure 46-3 summarizes some of the principal features in the above process.

Other small monomeric GTPases (eg, ARF, Rab, Ras, and Rho) are important in various cellular processes such as vesicle formation and transport (ARF and Rab; see below), certain growth and differentiation processes (Ras), and formation of the actin cytoskele-ton. A process involving GTP and GDP is also crucial in the transport of proteins across the membrane of the ER (see below).

Targeting

Docking

@ Recycle factors

RanGTP

RanGTP

RanGDP

Translocation

Translocation

RanGDP

Figure 46-3. Schematic representation of the proposed role of Ran in the import of cargo carrying an NLS signal. (1) The targeting complex forms when the NLS receptor (a, an importin) binds NLS cargo and the docking factor (P). (2) Docking occurs at filamentous sites that protrude from the NPC. Ran-GDP docks independently. (3) Transfer to the translocation channel is triggered when a RanGEF converts Ran-GDP to Ran-GTP. (4) The NPC catalyzes translocation of the targeting complex. (5) Ran-GTP is recycled to Ran-GDP by docked RanGAP. (6) Ran-GTP disrupts the targeting complex by binding to a site on P that overlaps with a binding site. (7) NLS cargo dissociates from a, and Ran-GTP may dissociate from p. (8) a and P factors are recycled to the cytoplasm. Inset: The Ran translocation switch is off in the cytoplasm and on in the nucleus. Ran-GTP promotes NLS- and NES-directed translocation. However, cytoplasmic Ran is enriched in Ran-GDP (OFF) by an active RanGAP, and nuclear pools are enriched in Ran-GTP (ON) by an active GEF. RanBP1 promotes the contrary activities of these two factors. Direct linkage of nuclear and cytoplasmic pools of Ran occurs through the NPC by an unknown shuttling mechanism. P|, inorganic phosphate; NLS, nuclear localization signal; NPC, nuclear pore complex; GEF, guanine nucleotide exchange factor; GAP, guanine-activating protein; NES, nuclear export signal; BP, binding protein. (Reprinted, with permission, from Goldfarb DS: Whose finger is on the switch? Science 1997;276:1814.)

Proteins similar to importins, referred to as ex-portins, are involved in export of many macromole-cules from the nucleus. Cargo molecules for export carry nuclear export signals (NESs). Ran proteins are involved in this process also, and it is now established that the processes of import and export share a number of common features.

MOST CASES OF ZELLWEGER SYNDROME ARE DUE TO MUTATIONS IN GENES INVOLVED IN THE BIOGENESIS OF PEROXISOMES

The peroxisome is an important organelle involved in aspects of the metabolism of many molecules, including fatty acids and other lipids (eg, plasmalogens, cholesterol, bile acids), purines, amino acids, and hydrogen peroxide. The peroxisome is bounded by a single membrane and contains more than 50 enzymes; catalase and urate oxidase are marker enzymes for this organelle. Its proteins are synthesized on cytosolic polyribosomes and fold prior to import. The pathways of import of a number of its proteins and enzymes have been studied, some being matrix components and others membrane components. At least two peroxisomal-matrix targeting sequences (PTSs) have been discovered. One, PTS1, is a tripeptide (ie, Ser-Lys-Leu [SKL], but variations of this sequence have been detected) located at the car-boxyl terminal of a number of matrix proteins, including catalase. Another, PTS2, consisting of about 26-36 amino acids, has been found in at least four matrix proteins (eg, thiolase) and, unlike PTS1, is cleaved after entry into the matrix. Proteins containing PTS1 sequences form complexes with a soluble receptor protein (PTS1R) and proteins containing PTS2 sequences complex with another, PTS2R. The resulting complexes then interact with a membrane receptor, Pexl4p. Proteins involved in further transport of proteins into the matrix are also present. Most peroxisomal membrane proteins have been found to contain neither of the above two targeting sequences, but apparently contain others. The import system can handle intact oligomers (eg, tetrameric catalase). Import of matrix proteins requires ATP, whereas import of membrane proteins does not.

Interest in import of proteins into peroxisomes has been stimulated by studies on Zellweger syndrome. This condition is apparent at birth and is characterized by profound neurologic impairment, victims often dying within a year. The number of peroxisomes can vary from being almost normal to being virtually absent in some patients. Biochemical findings include an accumulation of very long chain fatty acids, abnormalities of the synthesis of bile acids, and a marked reduction of plasmalogens. The condition is believed to be due to mutations in genes encoding certain proteins—so called peroxins—involved in various steps of peroxi-some biogenesis (such as the import of proteins described above), or in genes encoding certain peroxiso-mal enzymes themselves. Two closely related conditions are neonatal adrenoleukodystrophy and infantile Refsum disease. Zellweger syndrome and these two conditions represent a spectrum of overlapping features, with Zellweger syndrome being the most severe (many proteins affected) and infantile Refsum disease the least severe (only one or a few proteins affected). Table 46-2 lists some features of these and related conditions.

THE SIGNAL HYPOTHESIS EXPLAINS HOW POLYRIBOSOMES BIND TO THE ENDOPLASMIC RETICULUM

As indicated above, the rough ER branch is the second of the two branches involved in the synthesis and sorting of proteins. In this branch, proteins are synthesized on membrane-bound polyribosomes and translocated into the lumen of the rough ER prior to further sorting (Figure 46-2).

The signal hypothesis was proposed by Blobel and Sabatini partly to explain the distinction between free and membrane-bound polyribosomes. They found that proteins synthesized on membrane-bound polyribo-somes contained a peptide extension (signal peptide)

Table 46-2. Disorders due to peroxisomal abnormalities.1

MIM Number2

Zellweger syndrome

214100

Neonatal adrenoleukodystrophy

202370

Infantile Refsum disease

266510

Hyperpipecolic acidemia

239400

Rhizomelic chondrodysplasia punctata

215100

Adrenoleukodystrophy

300100

Pseudo-neonatal adrenoleukodystrophy

264470

Pseudo-Zellweger syndrome

261510

Hyperoxaluria type 1

259900

Acatalasemia

115500

Glutaryl-CoA oxidase deficiency

231690

Reproduced, with permission, from Seashore MR, Wappner RS: Genetics in Primary Care & Clinical Medicine. Appleton & Lange, 1996.

2MIM = Mendelian Inheritance in Man. Each number specifies a reference in which information regarding each of the above conditions can be found.

at their amino terminals which mediated their attachment to the membranes of the ER. As noted above, proteins whose entire synthesis occurs on free polyribosomes lack this signal peptide. An important aspect of the signal hypothesis was that it suggested—as turns out to be the case—that all ribosomes have the same structure and that the distinction between membrane-bound and free ribosomes depends solely on the former's carrying proteins that have signal peptides. Much evidence has confirmed the original hypothesis. Because many membrane proteins are synthesized on membrane-bound polyribosomes, the signal hypothesis plays an important role in concepts of membrane assembly. Some characteristics of signal peptides are summarized in Table 46-3.

Figure 46-4 illustrates the principal features in relation to the passage of a secreted protein through the membrane of the ER. It incorporates features from the original signal hypothesis and from subsequent work. The mRNA for such a protein encodes an amino terminal signal peptide (also variously called a leader sequence, a transient insertion signal, a signal sequence, or a presequence). The signal hypothesis proposed that the protein is inserted into the ER membrane at the same time as its mRNA is being translated on polyribo-somes, so-called cotranslational insertion. As the signal peptide emerges from the large subunit of the ribo-some, it is recognized by a signal recognition particle (SRP) that blocks further translation after about 70 amino acids have been polymerized (40 buried in the large ribosomal subunit and 30 exposed). The block is referred to as elongation arrest. The SRP contains six proteins and has a 7S RNA associated with it that is closely related to the Alu family of highly repeated DNA sequences (Chapter 36). The SRP-imposed block is not released until the SRP-signal peptide-polyribo-some complex has bound to the so-called docking protein (SRP-R, a receptor for the SRP) on the ER membrane; the SRP thus guides the signal peptide to the SRP-R and prevents premature folding and expulsion of the protein being synthesized into the cytosol.

The SRP-R is an integral membrane protein composed of a and P subunits. The a subunit binds GDP

Table 46-3. Some properties of signal peptides.

• Usually, but not always, located at the amino terminal

• Contain approximately 12-35 amino acids

• Methionine is usually the amino terminal amino acid

• Contain a central cluster of hydrophobic amino acids

• Contain at least one positively charged amino acid near their amino terminal

• Usually cleaved off at the carboxyl terminal end of an Ala residue by signal peptidase and the P subunit spans the membrane. When the SRP-signal peptide complex interacts with the receptor, the exchange of GDP for GTP is stimulated. This form of the receptor (with GTP bound) has a high affinity for the SRP and thus releases the signal peptide, which binds to the translocation machinery (translocon) also present in the ER membrane. The a subunit then hydrolyzes its bound GTP, restoring GDP and completing a GTP-GDP cycle. The unidirectionality of this cycle helps drive the interaction of the polyribosome and its signal peptide with the ER membrane in the forward direction.

The translocon consists of a number of membrane proteins that form a protein-conducting channel in the ER membrane through which the newly synthesized protein may pass. The channel appears to be open only when a signal peptide is present, preserving conductance across the ER membrane when it closes. The conductance of the channel has been measured experimentally. Specific functions of a number of components of the translocon have been identified or suggested. TRAM (translocating chain-associated membrane) protein may bind the signal sequence as it initially interacts with the translocon and the Sec61p complex (consisting of three proteins) binds the heavy subunit of the ribosome.

The insertion of the signal peptide into the conducting channel, while the other end of the parent protein is still attached to ribosomes, is termed "cotranslational insertion." The process of elongation of the remaining portion of the protein probably facilitates passage of the nascent protein across the lipid bilayer as the ribosomes remain attached to the membrane of the ER. Thus, the rough (or ribosome-studded) ER is formed. It is important that the protein be kept in an unfolded state prior to entering the conducting channel—otherwise, it may not be able to gain access to the channel.

Ribosomes remain attached to the ER during synthesis of signal peptide-containing proteins but are released and dissociated into their two types of subunits when the process is completed. The signal peptide is hydrolyzed by signal peptidase, located on the luminal side of the ER membrane (Figure 46-4), and then is apparently rapidly degraded by proteases.

Cytochrome P450 (Chapter 53), an integral ER membrane protein, does not completely cross the membrane. Instead, it resides in the membrane with its signal peptide intact. Its passage through the membrane is prevented by a sequence of amino acids called a halt- or stop-transfer signal.

Secretory proteins and proteins destined for membranes distal to the ER completely traverse the membrane bilayer and are discharged into the lumen of the ER. ^-Glycan chains, if present, are added (Chapter 47) as these proteins traverse the inner part of the ER membrane—a process called "cotranslational glycosyla-tion." Subsequently, the proteins are found in the

Figure 46-4. Diagram of the signal hypothesis for the transport of secreted proteins across the ER membrane. The ribosomes synthesizing a protein move along the messenger RNA specifying the amino acid sequence of the protein. (The messenger is represented by the line between 5' and 3'.) The codon AUG marks the start of the message for the protein; the hatched lines that follow AUG represent the codons for the signal sequence. As the protein grows out from the larger ribosomal subunit, the signal sequence is exposed and bound by the signal recognition particle (SRP). Translation is blocked until the complex binds to the "docking protein," also designated SRP-R (represented by the solid bar) on the ER membrane. There is also a receptor (open bar) for the ribosome itself. The interaction of the ribosome and growing peptide chain with the ER membrane results in the opening of a channel through which the protein is transported to the interior space of the ER. During translocation, the signal sequence of most proteins is removed by an enzyme called the "signal peptidase," located at the luminal surface of the ER membrane. The completed protein is eventually released by the ribosome, which then separates into its two components, the large and small ribosomal subunits. The protein ends up inside the ER. See text for further details. (Slightly modified and reproduced, with permission, from Marx JL: Newly made proteins zip through the cell. Science 1980;207:164. Copyright © 1980 by the American Association for the Advancement of Science.)

lumen of the Golgi apparatus, where further changes in glycan chains occur (Figure 47-9) prior to intracellular distribution or secretion. There is strong evidence that the signal peptide is involved in the process of protein insertion into ER membranes. Mutant proteins, containing altered signal peptides in which a hydrophobic amino acid is replaced by a hydrophilic one, are not inserted into ER membranes. Nonmembrane proteins (eg, a-globin) to which signal peptides have been attached by genetic engineering can be inserted into the lumen of the ER or even secreted.

There is considerable evidence that a second trans-poson in the ER membrane is involved in retrograde transport of various molecules from the ER lumen to the cytosol. These molecules include unfolded or mis-folded glycoproteins, glycopeptides, and oligosaccha-rides. Some at least of these molecules are degraded in proteasomes. Thus, there is two-way traffic across the ER membrane.

PROTEINS FOLLOW SEVERAL ROUTES TO BE INSERTED INTO OR ATTACHED TO THE MEMBRANES OF THE ENDOPLASMIC RETICULUM

The routes that proteins follow to be inserted into the membranes of the ER include the following.

A. Cotranslational Insertion_

Figure 46-5 shows a variety of ways in which proteins are distributed in the plasma membrane. In particular, the amino terminals of certain proteins (eg, the LDL receptor) can be seen to be on the extracytoplasmic face, whereas for other proteins (eg, the asialoglycoprotein receptor) the carboxyl terminals are on this face. To explain these dispositions, one must consider the initial biosynthetic events at the ER membrane. The LDL receptor enters the ER membrane in a manner analogous to a secretory protein (Figure 46-4); it partly traverses

LDL receptor HLA-A heavy chain Influenza hemagglutinin

Figure 46-5. Variations in the way in which proteins are inserted into membranes. This schematic representation, which illustrates a number of possible orientations, shows the segments of the proteins within the membrane as a-helices and the other segments as lines. The LDL receptor, which crosses the membrane once and has its amino terminal on the exterior, is called a type I transmembrane protein. The asialoglycoprotein receptor, which also crosses the membrane once but has its carboxyl terminal on the exterior, is called a type II transmembrane protein. The various transporters indicated (eg, glucose) cross the membrane a number of times and are called type III transmembrane proteins; they are also referred to as polytopic membrane proteins. (N, amino terminal; C, carboxyl terminal.) (Adapted, with permission, from Wickner WT, Lodish HF: Multiple mechanisms of protein insertion into and across membranes. Science 1985;230:400. Copyright © 1985 by the American Association for the Advancement of Science.)

the ER membrane, its signal peptide is cleaved, and its amino terminal protrudes into the lumen. However, it is retained in the membrane because it contains a highly hydrophobic segment, the halt- or stop-transfer signal. This sequence forms the single transmembrane segment of the protein and is its membrane-anchoring domain. The small patch of ER membrane in which the newly synthesized LDL receptor is located subsequently buds off as a component of a transport vesicle, probably from the transitional elements of the ER (Figure 46-2). As described below in the discussion of asymmetry of proteins and lipids in membrane assembly, the disposition of the receptor in the ER membrane is preserved in the vesicle, which eventually fuses with the plasma membrane. In contrast, the asialoglycoprotein receptor possesses an internal insertion sequence, which inserts into the membrane but is not cleaved. This acts as an anchor, and its carboxyl terminal is extruded through the membrane. The more complex disposition of the transporters (eg, for glucose) can be explained by the fact that alternating transmembrane a-helices act as un-

cleaved insertion sequences and as halt-transfer signals, respectively. Each pair of helical segments is inserted as a hairpin. Sequences that determine the structure of a protein in a membrane are called topogenic sequences. As explained in the legend to Figure 46-5, the above three proteins are examples of type I, type II, and type III transmembrane proteins.

B. Synthesis on Free Polyribosomes & Subsequent Attachment to the Endoplasmic Reticulum Membrane_

An example is cytochrome b5, which enters the ER membrane spontaneously.

C. Retention at the Luminal Aspect of the Endoplasmic Reticulum by Specific Amino Acid Sequences_

A number of proteins possess the amino acid sequence KDEL (Lys-Asp-Glu-Leu) at their carboxyl terminal.

This sequence specifies that such proteins will be attached to the inner aspect of the ER in a relatively loose manner. The chaperone BiP (see below) is one such protein. Actually, KDEL-containing proteins first travel to the Golgi, interact there with a specific KDEL receptor protein, and then return in transport vesicles to the ER, where they dissociate from the receptor.

D. Retrograde Transport From the Golgi Apparatus_

Certain other non-KDEL-containing proteins destined for the membranes of the ER also pass to the Golgi and then return, by retrograde vesicular transport, to the ER to be inserted therein (see below).

The foregoing paragraphs demonstrate that a variety of routes are involved in assembly of the proteins of the ER membranes; a similar situation probably holds for other membranes (eg, the mitochondrial membranes and the plasma membrane). Precise targeting sequences have been identified in some instances (eg, KDEL sequences).

The topic of membrane biogenesis is discussed further later in this chapter.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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