ElShamah - Reason & Science: Defending ID and the Christian Worldview
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ElShamah - Reason & Science: Defending ID and the Christian Worldview

Otangelo Grasso: This is my library, where I collect information and present arguments developed by myself that lead, in my view, to the Christian faith, creationism, and Intelligent Design as the best explanation for the origin of the physical world.

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Signal Recognition Particle: An essential protein targeting machine

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Signal Recognition Particle: An essential protein targeting machine 1


The argument of the zip-codes within the cell
1.  Michael Denton compared the cell to a city.  He writes: “To grasp the reality of life as it has been revealed by molecular biology, we must magnify a cell a thousand million times until it is twenty kilometers in diameter and resembles a giant airship large enough to cover a great city like London or New York.  What we would then see would be an object of unparalleled complexity and adaptive design.... a world of supreme technology and bewildering complexity.”
2. This has become more than true by discovering new details in the mind-boggling complex life of the cell. Proteins are the workhorses of the cell, but to get the most work out of them, they need to be in the right place.  In neurons, for example, proteins needed at axons differ from those needed at dendrites, while in budding yeast cells, the daughter cell needs proteins the mother cell does not.  In each case, one strategy for making sure a protein gets where it belongs is to shuttle its messenger RNA to the right spot before translating it. The destination for such an mRNA is encoded in a set of so-called “zipcode” elements, which loop out of the RNA string to link up with RNA-binding proteins.  In yeast, these proteins join up with a myosin motor that taxis the complex to the encoded location.
3. All the above speaks about amazing, irreducible complexity and intelligent design of one of the simplest cells, the yeast. How this complex system evolved was not explained. This complexity found in the simple cell of yeast is one more example out of innumerable complex systems that are necessary for the existence of the cell. 
4. The irreducibly complex systems are evidence of an intelligent design that could have been made only by a super-intelligent person all men call God.


Proteins destined for the cell membrane carry a marker sequence much in the way nuclear proteins carry an NLS. When the ribosome detects the marker sequence, it moves to the surface of the ER where it threads the protein through a pore as it is being synthesized. Ribosomes, located on the surface of the ER, can be clearly seen in electron micrographs; those areas are referred to as the rough ER. Once the protein is inside the ER, it is glycosylated by
several different enzymes that add the sugar molecules sequentially. This is analogous to a team of painters working on the same canvas. One painter might lay in the sky and ground, after which another paints the clouds and rocks. The glycosylating enzymes seem to follow a set of rules, because the same kinds of glycoproteins are produced over and over again, but the nature of those rules is still unclear. When the enzymes in the ER are finished, the glycoprotein is loaded into a transport vesicle (bubble) and sent to the Golgi complex. 6

All the difficulties and uncertainties of evolutionary reconstructions notwithstanding, parsimony analysis combined with less formal efforts on the reconstruction of the deep past of particular functional systems leave no serious doubts that LUCA already possessed at least several hundred genes.  In addition to the aforementioned “golden 100” genes involved in expression, this diverse gene complement consists of numerous metabolic enzymes, including  the subunits of the signal recognition particle (SRP)  3

Targeting of proteins to appropriate subcellular compartments is a crucial process in all living cells. Secretory and membrane proteins usually contain an amino-terminal signal peptide, which is recognized by the signal recognition particle (SRP) when nascent polypeptide chains emerge from the ribosome. 4

The Signal recognition particle (SRP) and its receptor comprise a universally conserved and essential cellular machinery that couples the synthesis of nascent proteins to their proper membrane localization. The past decade has witnessed an explosion in in-depth mechanistic investigations of this targeting machine at increasingly higher resolution. In this review, we summarize recent work that elucidates how the SRP and SRP receptor interact with the cargo protein and the target membrane, respectively, and how these interactions are coupled to a novel GTPase cycle in the SRP•SRP receptor complex to provide the driving force and enhance the fidelity of this fundamental cellular pathway

Proper localization of proteins to their correct cellular destinations is essential for sustaining the order and organization in all cells. Roughly 30% of the proteome is initially destined for the eukaryotic endoplasmic reticulum (ER), or the bacterial plasma membrane. Although the precise number of proteins remains to be determined, it is generally recognized that the majority of these proteins are delivered by the Signal Recognition Particle (SRP), a universally conserved protein targeting machine (1–4). 

The cotranslational SRP pathway minimizes the aggregation or misfolding of nascent proteins before they arrive at their cellular destination, and is therefore highly advantageous in the targeted delivery of membrane and secretory proteins. Despite the divergence of targeting machinery, the SRP pathway illustrates several key features that are general to almost all protein targeting processes: 

(i) the cellular destination of a protein is dictated by its ‘signal sequence’, which allows it to engage a specific targeting machinery; 
(ii) targeting factors cycle between the cytosol and membrane, acting catalytically to bring cargo proteins to translocation sites at the target membrane; and 
(iii) targeting requires the accurate coordination of multiple dynamic events including cargo loading/unloading, targeting complex assembly/disassembly, and the productive handover of cargo from the targeting to translocation machinery. 

Question : How could and would the protein find its way to the right destination without the signal sequence just right, right from the beginning ? 

Not surprisingly, such molecular choreography requires energy input, which is often harnessed by GTPase or ATPase modules in the targeting machinery. 

Cargo Recognition by the SRP

Timely recognition of signal sequences by the SRP is essential for proper initiation of cotranslational protein targeting. Signal sequences that engage the SRP are characterized, in general, by a core of 8–12 hydrophobic amino acids. 

The multiple conformational rearrangements in the SRP•FtsY GTPase complex provide a series of additional checkpoints to further reject the incorrect cargos. These include: 

(i) formation of the early intermediate, which is stabilized over 100-fold by the correct, but not incorrect cargos (Figure 3B, red arrow b); 
(ii) rearrangement of the early intermediate to the closed complex, which is ~10-fold faster with the correct than the incorrect cargos (Figure 3B, red arrow c); and 
(iii) GTP hydrolysis by the SRP•FtsY complex, which is delayed ~8-fold by the correct cargo to give the targeting complex a sufficient time window to identify the membrane translocon.

In contrast, GTP hydrolysis remains rapid with the incorrect cargo (t1/2 < 1s), which could abort the targeting of incorrect cargos (Figure 3B, arrow d). A mathematical simulation based on the kinetic and thermodynamic parameters of each step strongly suggest that all these fidelity checkpoints are required to reproduce the experimentally observed pattern of substrate selection by the SRP (40).

These results support a novel model in which the fidelity of protein targeting by the SRP is achieved through the cumulative effect of multiple checkpoints, by using a combination of mechanisms including 

cargo binding, induced SRP–SR assembly, and kinetic proofreading through GTP hydrolysis.  Additional discrimination could be provided by the SecYEG machinery, which further rejects the incorrect cargos (102).  Analogous principles have been demonstrated in the DNA and RNA polymerases (103104), the spliceosome (105), tRNA synthetases (106) and tRNA selection by the ribosome (107), and may represent a general principle for complex biological pathways that need to distinguish between the correct and incorrect substrates based on minor differences.

The crowded ribosome exit site

Accumulating data now indicate that the ribosome exit site is a crowded environment where multiple protein biogenesis factors interact. As a newly synthesized protein emerges from the ribosomal exit tunnel, it interacts with a host of cellular factors that facilitate its folding, localization, maturation, and quality control. These include molecular chaperones.


Many proteins need to enter the ER for modification with sugars this occurs at the same time that they are being synthesized by the ribosome translation begins with synthesis of a short signal peptide sequence a signal recognition particle a protein complex binds to the signal peptide while translation continues the SRP then binds to its receptor in the ER membrane anchoring the ribosome the ribosome binds its receptor and the signal peptide meets the protein translocator translation proceeds and the protein passes through the translocator the signal peptidase cleaves the signal peptide leaving the new protein molecule in the lumen of the endoplasmic reticulum

A non-mechanical example of irreducible complexity can be seen in the system that targets proteins for delivery to subcellular compartments. In order to find their way to the compartments where they are needed to perform specialized tasks, certain proteins contain a special amino acid sequence near the beginning called a 'signal sequence.'' As the proteins are being synthesized by ribosomes, a complex molecular assemblage called the signal recognition particle or SRP, binds to the signal sequence. This causes synthesis of the protein to halt temporarily. During the pause in protein synthesis the SRP is bound by the transmembrane SRP receptor, which causes protein synthesis to resume and which allows passage of the protein into the interior of the endoplasmic reticulum (ER). As the protein passes into the ER the signal sequence is cut off. For many proteins the ER is just a way station on their travels to their final destinations (Figure 10.3). 

Signal Recognition Particle: An essential protein targeting machine Uyvz8yJ

Proteins which will end up in a lysosome are enzymatically ``tagged'' with a carbohydrate residue called mannose- 6-phosphate while still in the ER. An area of the ER membrane then begins to concentrate several proteins; one protein, clathrin, forms a sort of geodesic dome called a coated vesicle which buds off from the ER. In the dome there is also a receptor protein which binds to both the clathrin and to the mannose-6-phosphate group of the protein which is being transported. The coated vesicle then leaves the ER, travels through the cytoplasm, and binds to the lysosome through another specific receptor protein. Finally, in a maneuver involving several more proteins, the vesicle fuses with the lysosome and the protein arrives at its destination. During its travels our protein interacted with dozens of macromolecules to achieve one purpose: its arrival in the lysosome. 

Virtually all components of the transport system are necessary for the system to operate, and therefore the system is irreducible. And since all of the components of the system are comprised of single or several molecules, there
are no black boxes to invoke. The consequences of even a single gap in the transport chain can be seen in the hereditary defect known as Icell disease. It results from a deficiency of the enzyme that places the mannose-6-phosphate on proteins to be targeted to the lysosomes. I-cell disease is characterized by progressive retardation, skeletal deformities, and early death.

Transport by vesicles: when proteins are made on the rough endoplasmic reticulum (RER), they get loaded into the Golgi apparatus. They are then sorted, modified and packaged in vesicles made from the budding-off of the Golgi membrane and discharged.
Sorting signals directs the protein to the organelle. The signal is usually a stretch of amino acid sequence of about 15-60 amino acids long.
There are at least three principles that characterize all vesicles mediated transport within cells:

i. The formation of membrane vesicles from a larger membrane occurs through the assistance of a protein coat such as clathrin that engulfs the protein because an adapter protein such as adaptin binds both to the coat and to the cargo protein bringing both close together. 5
The adaptin traps the cargo protein by biding with it’s receptors. After assembly particles bind to the clathrin protein they assemble into a basket-like network on the cytosolic surface of the membrane to shape it into a vesicle. Their final budding-off requires a GTP-binding protein called dynamin.
ii. The process is facilitated by a number of GTP-binding proteins (ex; dynamin) that assemble a ring around the neck of a vesicle and through the hydrolysis of the phosphate group of GTP to GDP until the vesicle pinches off. In other words, GTP is one of the main sources of cellular energy for vesicle movement and fusion.
iii. After a transport vesicle buds-off from the membrane, it is actively transported by motor proteins that move along cytoskeleton fibers to its destination. The vesicle then fuses with a target membrane and unloads the cargo (protein). But in order to fuse a vesicle with the membrane of another compartment, they both require complementary proteins, which in this case is soluble N-ethylmalei mide-sensitive-factor attachment protein receptor or, ahem, SNARE present in the membrane – one for the vesicle (vesicular SNARE) and one for the target membrane (t-SNARE).

Each organelle and each type of transport vesicle is believed to carry a unique SNARE. Interactions between complementary SNAREs helps ensure that transport vesicles fuse only with the correct membrane.
Membrane fusing does not always follow immediately after docking (unloading of cargo), however it often waits for specific molecular signals.
COP stands for Coatamer proteins (COP) which is the second class of coat protein that mediates budding-off of vesicles from large membranes. It can be of two types I (anterograde; moving in a forward direction. Ex; from ER to Golgi) & II (retrograde; moving in a backward direction. Ex: from Golgi back to ER).

Signal Recognition Particle: An essential protein targeting machine ZQwmEuw

Thirty years ago, the components and pathway for SRP-dependent protein targeting were first elucidated in mammalian cells through in vitro reconstitutions in cell extracts (5–9). The identification of the SRP homologue in prokaryotes a decade later further highlighted the salient, universally conserved features of this pathway (10–12). The biochemical accessibility of the bacterial SRP system has allowed for in-depth mechanistic investigations of this pathway, allowing us to understand its underlying molecular mechanism at unprecedented depth and resolution.

With the exception of the chloroplast SRP , SRP-mediated protein targeting is a strictly cotranslational process that begins when a nascent polypeptide destined for the ER or plasma membrane emerges from the ribosome (Fig. 1A).

Signal Recognition Particle: An essential protein targeting machine T9V1slO
Overview of the pathways and components of SRP. 
(A) Multiple pathways deliver newly synthesized proteins to the ER or plasma membrane, with the SRP pathway mediating the co-translational targeting of translating ribosomes (right) and post-translational targeting machineries mediating the targeting of proteins released from the ribosome. 
(B) Domain structures of the ribonucleoprotein core of SRP, comprised of the SRP54 (or Ffh) protein and the SRP RNA (left), and the bacterial SRP receptor (right).

The N-terminal signal sequence on the nascent polypeptide serves as the ‘signal’ that allows the ribosome•nascent chain complex (termed the RNC or cargo) to engage the SRP and, through interaction with the SRP receptor (SR), to be delivered to the vicinity of the Sec61p (or SecYEG in prokaryotes) translocon at the target membrane (Fig. 1A). There, the RNC is transferred to the Sec61p/SecYEG machinery, which either integrates the nascent polypeptide into the lipid bilayer or translocates it across the membrane to enter the secretory pathway. Meanwhile, SRP and SR dissociate from one another to mediate additional rounds of targeting (Fig. 1A).


1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805129/
2. Intelligent Design Creationism and Its Critics, page 251
3. Koonin, The logic of chance, page 331
4. https://sci-hub.bz/https://www.nature.com/articles/nature08870
5. https://animalcellbiology.wordpress.com/category/signal-recognition-particle/
6. The Cell, Panno, page 69


Last edited by Otangelo on Fri Sep 01, 2023 3:15 pm; edited 14 times in total




The protein export pathway of eukaryotes is highly conserved. Protozoa, yeast, and mammalian cells use essentially the same mechanisms to translocate proteins into an ER, to glycosylate and sort them in the Golgi, and to export them across the plasma membrane by exocytosis. 1

Translocation Across the ER Membrane

Translocation of newly synthesized proteins across the ER membrane shows many similarities to translocation across the plasma membrane protein of bacteria. Proteins are prevented from folding in the cytoplasm. They are fed across the plasma membrane through a translocon, a proteinaceous pore, which has three subunits very similar to the bacterial proteins made by the secY, E, and G genes. By electron microscopy, these pores are rings about 8 to 10 nm in diameter, with a

central pore of 2 nm, sufficient to allow the passage of an extended, hydrated peptide of 1.1 nm in diameter. These pores can now be recognized. In yeast, proteins traverse pores in the ER by two different types of translocation mechanisms. One is an ATP-driven process that translocates proteins whose synthesis is complete. The other couples translation to the translocation process. In this transport mode, the ribosome is attached to the proteinaceous transport pore, the translocon, and

feeds the nascent train through the pore as it is being synthesized. Mammalian cells only have the cotranslation made of translocation. When translocation is co-translational, the nascent chain is recognized in the cytoplasm by a signal recognition particle, which stops further protein synthesis until the complex of ribosome, nascent chain, and signal recognition particle reaches the endoplasmic reticulum

Behe, Black Box, page 103

A new protein, freshly made in the cell, encounters many molecular machines. Some of the machines grab hold of the protein and send it along to the location it is destined to reach. In a little while I will follow a protein along one pathway from start to finish. 3 The space probe is shaped like a huge sphere. Inside the sphere are a number of smaller, self-contained spheres, each of which holds machinery for specialized tasks. In the biggest of the interior spheres—let's call it the «library»—are the blueprints for making all the machines in the space probe. These are not ordinary blueprints, however. They can be thought of as blueprints in braille—or perhaps as sheet music for a player piano—where physical indentations in the blueprint cause a master machine to make the machine for which the blueprint codes.

One fine day the space probe senses (by some mechanism we'll ignore) that it needs to make another battery crusher and to send the newly made machine to work in the garbage treatment room, where it will help in recycling old batteries. So the process to do that is set in motion: The blueprint for the battery crusher is photocopied in the library, and the blueprint copy floats over to a window in the library (remember; there's no gravity). On the edge of the blueprint are punch holes arranged in a special pattern, which exactly matches pegs on a scanner mechanism at the window. When the blueprint hooks onto the scanner; the window door opens like the shutter of a camera. The blueprint jiggles loose of the scanner and floats out of the library into the main area of the probe.
In the main area are many machines and machine parts; nuts, bolts, and wires float freely about. In this section reside many copies of what are called master machines, whose job it is to make other machines. They do this by reading the punch holes in a blueprint, grabbing nuts, bolts, and other parts that are floating by, and mechanically assembling the machine piece by piece.
The blueprint for the battery crusher, floating in the main area, quickly comes in contact with a master machine. Whirring, turning appendages on the master machine grab some nuts and bolts and start assembling the crusher. Before it assembles the body of the crusher, however, the master machine first makes a temporary «ornament» that marks the crusher as a machine that has to leave the main area.

In the main area is another machine, called a guide. The shape of the guide is exactly complementary to the shape of the ornament, and little magnets on the guide allow it to attach securely. As the guide snuggles up to the ornament it pushes down on the master machine's switch, causing the master machine to halt its construction of the crusher.
On the outside of one of the interior spheres (we'll call the sphere «processing room #1») is a receiving site that has a shape complementary to part of the guide and part of the ornament. When the guide, ornament, and attached parts bump into that shaped section, the master machine's switch is flipped back on, causing construction of the crusher to resume.
Right next to that shaped section is a window. When the ornament taps on the window (there's a lot of jostling going on), it activates a conveyor belt inside the processing room and the conveyor belt pulls the new battery crusher inside the processing room, leaving the master machine, blueprint, and guide on the outside.

As the crusher was being pulled through the window another machine removed the now-unnecessary ornament. Now, amazingly, constriction machines embedded in the flexible walls of processing room #1 cause a section of the wall to close in on and surround some of the machines, forming a new, free-floating subroom. The remainder of the wall that was left behind smoothly seals itself.
The subroom now floats a short distance through the main area before bumping into a second processing room. The subroom merges with the wall, and spills its contents into processing room #2. The battery crusher then passes through processing rooms #3 and #4 by mechanisms similar to those that took it from room #1 to room #2. It is in the processing rooms that machines receive the tags that direct them to their final destinations. An antenna is placed on the battery crusher and quickly trimmed down to make a very special configuration; the special shape of the trimmed antenna will tell other mechanisms to direct the crusher to the garbage treatment room.

In the wall of the last processing room are machines («haulers») with a shape complementary to that of the trimmed antenna of the battery crusher. The crusher sticks to the haulers, and that area of the wall begins to pinch off to form a subroom. Outside the subroom is another machine (the «delivery coder») with a shape that exactly complements the shape of a machine (the «port marker») sticking out of the garbage treatment room. The sub-room hooks up to the garbage treatment room through the two complementary machines. Another machine (the «gateway») then drifts by. The gateway has a shape that is complementary to a portion of the delivery coder and the port marker. When it sticks to them the gateway punches a small hole in the garbage treatment room, and the transit sphere merges with it, dumping its contents into the disposal. The battery crusher is able to begin its work.

Perhaps by this point in the book, the reader can easily see how the transport system that sent the battery crusher to its destination is irreducibly complex. If any of its numerous components is missing, then the crusher is not delivered to the garbage treatment room. Furthermore, the delicate balance of the system must be maintained; each of the many components that interlock must do so precisely and then disengage, and each must arrive and depart at the proper times. Any single error will cause the system to fail.

All of the fantastic machines in our space probe have direct counterparts in the cell. The space probe itself is the cell, the library is the nucleus, the blueprint is the DNA, the copy of the blueprint is RNA, the window of the library is the nuclear pore, the master machines are ribosomes, the main area is the cytoplasm, the ornament is the signal sequence, the battery crusher is a lysosomal hydrolase, the guide is the signal recognition particle (SRP), the receiving site is the SRP receptor, processing room 1 is the endoplasmic reticulum (ER), processing rooms 2 through 4 are the Golgi apparatus, the antenna is a complex carbohydrate, the sub-rooms are coatomer or clathrin-coated vesicles, and various proteins play the roles of the trimmer, hauler, delivery coder, port marker, and gateway. The garbage treatment room is the lysosome.

Let's quickly run through a description of how a protein that is synthesized in the cytoplasm eventually finds its way to the lysosome. This will take just one paragraph. Don't worry if you rapidly forget the names and procedures of cellular transport; the purpose is simply to give you a glimpse of the cell's complexity.

1. The encyclopedia of molecular biology




Signal Recognition Particle: An essential protein targeting machine Signal13
Signal Recognition Particle: An essential protein targeting machine Signal10
Signal Recognition Particle: An essential protein targeting machine Signal11
Signal Recognition Particle: An essential protein targeting machine Signal14
Signal Recognition Particle: An essential protein targeting machine Signal12
Signal Recognition Particle: An essential protein targeting machine Signal15




Yale Researcher Identifies Structure of Molecular "Zip Code" Reader


Yale researchers have discovered that a critical function of each cell – passing proteins through a membrane – is performed as a duet, not a solo.

An article published in the current issue of Science and featured on the cover describes the structure involved in the process, which is the signal recognition particle (SRP), said Jennifer Doudna, professor of molecular biophysics and biochemistry.

The SRP is made up of a protein and an RNA molecule.

What is surprising, Doudna said, is that the SRP structure suggests a role for the RNA in direct recognition of the signal peptide.

“What we think happens is that the RNA and the protein in the SRP work together to recognize the signal peptide,” Doudna said. “Previously it’s been thought that the functions of the proteins and the RNA were separate. Here we are seeing an example of true molecular collusion.”

The signal peptide within the cell is a molecular zip code that identifies the proteins that have to go through a membrane. “This paper,” she said, “describes the molecular structure of the machine that reads the zip code, which is the SRP. It reads the zip code, binds to the protein, and then transports the protein to the membrane of the cell.”

Doudna said it is not clear why the SRP has an RNA molecule.

When we look at evolution from the three major kingdoms of life – bacteria, eukaryotes, and archaea – all have SRP and the same RNA that is part of the SRP,” she said. “Our lab has been interested in the role of RNA molecules in a variety of different biological functions. This current structure describes what the SRP looks like.”

The SRP sample used in the Yale project was taken from E coli bacteria and represents what would be found in humans and other organisms because of the SRP’s high degree of evolutionary conservation.

“The next step is to test the hypotheses we now have about the role of RNA in the SRP,” Doudna said. “One way we’re doing that is to see if we can introduce the signal peptide into crystals we have of the SRP core. The other thing we would like to know is how this part of the SRP is regulated.”




Soluble Proteins Made on the ER Are Released into the ER Lumen

Two protein components help guide ER signal sequences to the ER membrane:

(1) a signal-recognition particle (SRP), present in the cytosol, binds to both the ribosome and the ER signal sequence as it emerges from the ribosome; and
(2) an SRP receptor, embedded in the ER membrane, recognizes the SRP.

Binding of an SRP to a ribosome that displays an ER signal sequence slows protein synthesis by that ribosome until the SRP engages with an SRP receptor on the ER. Once bound, the SRP is released, the receptor passes the ribosome to a protein translocator in the ER membrane, and protein synthesis recommences. The polypeptide is then threaded across the ER membrane through a channel in the translocator.

Signal Recognition Particle: An essential protein targeting machine Signal10

The SRP and SRP receptor thus function as molecular matchmakers, bringing together ribosomes that are synthesizing proteins with an ER signal sequence and protein translocators within the ER membrane. In addition to directing proteins to the ER, the signal sequence—which for soluble proteins is almost always at the N-terminus, the end synthesized first—functions to open the protein translocator. This sequence remains bound to the translocator, while the rest of the polypeptide chain is threaded through the membrane as a large loop. The signal sequence is removed by a transmembrane signal peptidase, which has an active site facing the lumenal side of the ER membrane. The cleaved signal sequence is then released from the protein translocator into the lipid bilayer and rapidly degraded. Once the C-terminus of a soluble protein has passed through the translocator, the protein is released into the ER lumen




An informal name for a molecular cell biology system of signals or "address tags" that guide the movement of a protein within a cell. In more technical terms, protein ZIP codes* are molecular signals that direct the protein from the endoplasmic reticulum, where it is assembled, to the cytoplasm of the cell and into other cellular compartments such as the nucleus of the cell.






Many proteins function in the cytoplasm where they are produced. These proteins probably need little information targeting them to specific locations. But a large number of proteins must arrive at specific destinations within or outside of the cell in order to function. For example, some proteins are designated to function within the membrane of the endoplasmic reticulum of the cell. Others must be secreted to the outside of the cell, or perhaps in the outer or inner membrane of the mitochondrion , the intramembranous space, or into the mitochondrial matrix. Correct targeting of the protein to each of these different space areas requires explicit instructions within the targeted protein.

In the case of the mitochondrion, an organelle of the cell responsible for converting stored energy into ATP, there are four distinct target areas. Although the mitochondrion has its own DNA and protein synthesizing equipment, most of the mitochondrial proteins are made from DNA contained in the nucleus of the cell. These proteins are produced in the cytoplasm, and must navigate from there into the correct compartment of the mitochondrion .

The mitochondrion contains four different target areas that must be separately coded in the protein. The matrix is the site of most of the metabolic activity, and of most of the proteins of the mitochondrion. Both inner and outer membranes are separately targeted by a variety of other proteins, and the intermembrane space is the site for several of the cytochromes..

The targeting processes are complex, and some of the details are still being elaborated, but many of the features are well understood.

Each compartment of the mitochondrion is handled by a different set of signals and signal receptors, with the result that each protein arrives at the correct destination.

how did these signal receptors evolve ?

Some proteins must remain within the membrane, either the endoplasmic reticulum, or the outer cell membrane, or in some other cellular membrane. Such proteins play a vital role in regulating the passage of materials through the membrane, and in other vital cellular processes. In order for the protein to be produced in this configuration, the gene for its production must contain, in addition to the usual information on how to build an active functional protein, a variety of instructions informing the cell as to what destination and pathway the protein must follow.

how did these instructions evolve ?

One of the possible destinations for a protein is the outer cellular membrane. Proteins destined for this fate begin with a special set of instructions termed a signal. This system of signals are recognized by a special cytoplasmic body called the signal recognition particle (SRP)

The Signal-Recognition Particle (SRP) is part of a complex of proteins responsible for targeting proteins to specific compartments of the cell. The mechanisms, components and the targeting information appear to be universal, being recognized in plant, animal, and even yeast cells. Proteins destined for targets outside of the cytoplasm (either in membrane-bound compartments, or in the membranes themselves, or for secretion outside the cell), are designated by specific sequences of amino acids in the leader region of the protein. The particle responsible for identifying these specific sequences, called signal peptides in nascent (growing) proteins, is the SRP. This complex consists of a chain of 300 specific bases of RNA and six proteins, identified by their respective molecular weights (in kilodaltons): P9, P14, P54, P68 and P72. It is known that the P54 protein is responsible for reading and interacting with the signal peptide, the two small proteins interact with the ribosome, and the large P68/P72 proteins are involved in the movement of the nascent peptide chain. The SRP will stop protein synthesis after about 70 amino acid residues, in the absence of suitable membrane interactions, preventing the synthesis of proteins in inappropriate environments.

This particle identifies a coded message in the first 50 or so amino acids of non-cytoplasmic proteins as they are being produced by the ribosome, and binds to this leader sequence, referred to as the "signal peptide".


1. The Signal Receptor Particle (SRP)recognizes and binds to the emerging signal anchor sequence (red) of the nascent (growing) protein and integrates into the ribosome.

2. The integrated SRP engages a complex SRP receptor (alpha and beta proteins) in the membrane of the endoplasmic reticulum.

3. When thus anchored, the hydrolysis of GTP (Guanosine triphosphate) triggers the release of the SRP and the SRP receptor from the ribosome, opens the gate blocking the translocon, and inserts the nascent protein chain into the translocon. The translocon is a membrane complex made up of three or four sec61 complexes, each composed of three proteins (sec61 alpha, beta and gamma) The alpha protein is a membrane-spanning protein, making ten membrane crossings. Another major component of the translocon is the TRAM protein, which crosses the membrane at least eight times.

4. The ribosome is now anchored to the translocon by the growing peptide. As the peptide elongates, the helical signal-anchor sequence (red) extends through the membrane to the inner lumen.

5. When a second helical series of amino acids, the Stop-Transfer Membrane-Anchor Sequence (blue) is encountered, the movement of the growing peptide chain into the translocon ceases.

Molecules such as the voltage-gated sodium channel protein discussed below must have encoded within them all of the information for their functional and structural attributes, as well as information for acquiring their active domains, distributed throughout the entire length of the molecule.

This signaling mechanism is universal, since the processes operate in the same way in virtually all eukaryotic cells, including yeast, plant and animal cells. Further, the proteins comprising the translocon and the SRP receptor, that are responsible for the insertion of membrane-targeted proteins into the membrane are also multipass membrane-bound proteins. This means that they also must be inserted into the membrane by a similar mechanism. The universality means the proteins and the mechanism for their acquisition by membranes were already present in the first metazoans of record, and in the ancestral eukaryotc cell, as well.


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