Biology Essay Sample - Signal Sequence Hypothesis

Eukaryotic cells are complex cells that make up plants, fungi and animals. They have various compartments with each dedicated to a specific function. These compartments are elaborately distinguished from each other by layers of membrane. This aspect enables the compartments to maintain specific conditions necessary for their specified function. For example, lysosomes function as recycling centers for a cell and must therefore maintain an acidic pH in order to sieve away cellular waste (Margulis 1970). Similarly, peroxisomes house chemical reactions such as oxidation. Oxidation produces hydrogen peroxide which would damage the cell if not well contained.

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A cells proteins are synthesized by ribosomes. These include proteins to be included in the plasma membrane. One state, in which cytoplasmic ribosomes in eukaryotic cells occur, is the attached state. This involves ribosomes within the endoplasmic reticulum membranes. Through the works G. Blobel, D. Sabatini, M. Redman, C, Milstein, J. Rothman, J. Lenard, and H.Lodish, the mechanical processes of routing newly synthesized proteins to the required destinations in a cell has been understood more. In the 1970s Blobel and Sabatini proposed the confirmation of the signal hypothesis which was a major contribution the elaboration of the phenomena. They proposed that every secretory protein has a short sequence of amino acids at its N-terminal end, used as a signal to guide it to the endoplasmic reticulum membrane (Blobel et al, 1978).

The export from the endoplasmic reticulum depends on interactions between the export signal in the cytoplasmic ribsomes area of the load and a load recognition area on the protein complex. Diacidic and dihydrophbic motifs contribute to outstanding characterization of export motifs. Diacidic motifs presence has been established in several transmembrane proteins. This proteins include; vesicular stomatitis virus glycoprotein (VSV-G), cystic fibrosis transmembrane conductance regulator and inwardly rectifying potassium channels. Dihydrophobic are paramount in the endoplasmic reticulum export of ERGIC53. Endoplasmic reticulum has various export codes that include; the LXXLE motif of the yeast, syntaxin and GABA transporters (Kurzchalia et al 1986).

Signal sequence is a short peptide, usually 5-30 amino acids long that is located at the N-terminal of most of new proteins from the ribosomes that are destined to the secretory path. These include the proteins that are found either inside the endoplasmic reticulum, Golgi bodies or endosomes that are secreated from the cell or those that are introduced into most cellular membranes. Most type I membrane bound proteins contains signal sequences but majority of type II are aimed at secretory path by their first transmembrane domain (Bernstein et al 1989). The core of a signal sequence has a long stretch, around 5-16 residues long, of hydrophobic amino acids. It consistently forms a single alpha-helix also known as the h-region. Most signal sequences begin with a short positively charged stretch of amino acids which may be useful in ensuring the proper topology of the polypeptide during translocation by the positive-inside rule. In eukaryotic cells the signal sequences may follow co-translational or post-translational paths (Blobel et al 1975). A co-translational path is achieved when the signal sequence comes out of the ribosome and is recognized by the signal recognition particle. A post-translational path is realized when protein synthesis is complete. Signal sequences are heterogeneous, hence most eukaryotic signal sequences can be interchanged functionally between different species. However, it is important to note that the efficiency of protein secretion is subject to the signal sequence.

Contributing to the experimental evidence in 1967 was Palade, who discovered the ribosomes. He found out the intracellular path of secretion of proteins from the cells. He proved that the first step involved is the translocation of secretory proteins across the endoplasmic reticulum. It is then followed by the vesicular transport, and exocytosis at the plasma membrane. In 1999, Blobel established that indeed proteins have intrinsic signals that determine their locomotion and localization in the cell. He improved into deliberations that proteins ought to cross through membranes of other organelles. After setting up in vitro systems, he identified major elements such as signal recognition particle, its receptor in the endoplasmic reticulum, signal peptidases and a signal sequence-gated conducting channel. These techniques by Blobel are currently widely employed in laboratories around the world (Lingappa et al 1978).

The signal recognition particle is a protein complex that aims proteins towards the endoplasmic reticulum membrane. It is organized into S and Alu domains. An Alu domain consists of a translational arrest function and SRP9 and SRP14 proteins that are bound to the terminals of SRP RNA molecule. The knowhow on the SRP and its evolution in eukaryotes such as protozoa and yeast is still minimal. However, their genome sequences are now available and it is possible to analyze this information in relation to genes encoding SRP components. A eukaryotic SRP contains a 300 nucleotide 7S RNA and six proteins. In addition, eukaryotic consists of eight helical elements that fold into Alu and S domains that are separated by a long linker region. Mediation of the peptide chain elongation of retardation function the SRP is speculated enabled by the Alu domain. The human genome is proven to contain large amounts of SRP RNA related sequences, as well as Alu repeats (Nakai et al 1992).

The signal particle receptor otherwise known as a docking protein is a regulator that has two distinct subunits that are associated independently with the endoplasmic reticulum in mammalian cells. Its function, as the name suggests is to receive the SRP units. The eukaryotic SRP receptor is an all-round regulator of SR-alpha and SR-beta, both containing a GTP-binding domain. SRP- alpha is responsible for regulating the aiming of SRP-ribosome-nascent polypeptide complexes to the translocon. Interestingly, the existence of non-coding has never been related in the context of eukaryotic DNA and its evolution (Walter et al 1982).The RNA component is responsible for enhancing the interaction between SRP and its SR receptor. As noted earlier, SRP contains the Alu and S domains. They allow the SRP time to attach the ribosome polypeptide to the RER membrane.

Protein translocation into the endoplasmic reticulum membrane involves signal sequences. Depending on hydrophobia levels and amino acids concentration in the protein, transport can occur co-translationally or post-translationally. The two mechanisms meet at the endoplasmic reticulum membrane level. This happens at the all-inclusive trimetric sec61 complex available in the membrane. The sec61 makes available signal peptide recognition and initiates a polypeptide conducting channel. The channel is known as a translocon. This same complex is used in integration of nascent proteins into the membrane. In conclusion, proteins scheduled for translocation to the endoplasmic reticulum are recognized by the SRP. In turn, the SRP regulates translation of the polypeptide by the ribosome as it continues to attach the ribosome to the SRP receptor on the endoplasmic reticulum. The recognition is based on the N-terminal of the signal sequence.

Bibliography

Bernstein, H.D., Poritz, M.A., Strub, K., Hoben, P.J., Brenner, S. and Walter, P., 1989. Model for signal sequence recognition from amino-acid sequence of 54K subunit of signal recognition particle, Nature, 340(6233), pp.482-486.

Blobel, G., Walter, P., Chang, C.N., Goldman, B.M., Erickson, A.H. and Lingappa, V.R., 1978, December, Translocation of proteins across membranes: the signal hypothesis and beyond. In Symposia of the Society for Experimental Biology (Vol. 33, pp. 9-36).

Blobel, G.O.N.T.E.R. and Dobberstein, B., 1975. Transfer of proteins across membranes. J. Cell Biol, 67(835), p.852.

Kurzchalia, T.V., Wiedmann, M., Girshovich, A.S., Bochkareva, E.S., Bielka, H. and Rapoport, T.A., 1986. The signal sequence of nascent preprolactin interacts with the 54K polypeptide of the signal recognition particle, Nature, 320(6063), pp.634-636.

Lingappa, V.R., Katz, F.N., Lodish, H.F. and Blobel, G., 1978. A signal sequence for the insertion of a transmembrane glycoprotein. Similarities to the signals of secretory proteins in primary structure and function, Journal of Biological Chemistry, 253(24), pp.8667-8670.

Margulis, L., 1970. Origin of eukaryotic cells: evidence and research implications for a theory of the origin and evolution of microbial, plant, and animal cells on the Precambrian earth.

Nakai, K. and Kanehisa, M., 1992. A knowledge base for predicting protein localization sites in eukaryotic cells, Genomics, 14(4), pp.897-911.

Walter, P. and Blobel, G., 1982. Signal recognition particle contains a 7 S RNA essential for protein, Nature, 299, p.21.