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 SRPTimely 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 (103, 104), 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 siteAccumulating 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).
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).
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).
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).
2. Intelligent Design Creationism and Its Critics, page 251
3. Koonin, The logic of chance, page 331
6. The Cell, Panno, page 69
Last edited by Otangelo on Thu Jan 14, 2021 6:06 am; edited 12 times in total