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rRNA AND RIBOSOMES
rRNA is not unique to humans. rRNA is the primary constituent of ribosomes—those organelles which convert the genetic code into proteins in all living things. Comparisons of rRNA gene sequences link all living things, even those as different as prokaryotic cells and humans, in the same family tree. The multiple copies of the rRNA genes approach 1% of the number of human genes. Mitochondrial rRNA genes do not support that idea that mitochondria were “designed” for living cells, but rather that they have evolved from bacterial endosymbionts of early eukaryotic cells. The fact that rRNA performs a cellular function as RNA rather than as a code for protein which performs a certain function suggests that rRNA originated in the earliest cells from the RNA world.
At first glance, the following cells appear incredibly different.
The above photos of bacteria, the blood cells of a turtle, and human neurons obviously represent different kinds of cells. Upon closer examination, however, the similarities are remarkable. They are all composed of very similar kinds of molecules and, in all of them, proteins perform most of the essential functions of the cell—they make up the pumps, the channels, the cytoskeleton, the enzymes, the receptors, etc. All of them make these proteins in the same way—messenger RNA dictates the precise ordering of amino acids (bound to tRNAs) at an organelle called the ribosome. Not only are ribosomes of interest because proteins are made there, the structure of ribosomes offer a tantalizing glimpse into early life. The original function of the ribosome might have been RNA replication using trinucleotide RNA subunits (Martin, 2002a).
Many proteins are incorporated into the structure of a ribosome whose primary function seems to be the stabilization of the RNA structure. The sheer number of components of a ribosome and the observation that the genes for the components are not located in one site in the genome presents a regulatory challenge to cells. Proteins synthesis could arguably performed more efficiently if it were made entirely of protein, there were fewer components, and the genes organized as a unit to facilitate their regulation.
Translation occurs at ribosomes which are made of rRNA (ribosomal) and protein (it seems 3 types of rRNA and about 60-70 proteins are needed; rRNA makes up half the weight). Ribosomes must be assembled from several subunits (which are identified by their density measured in Svedburg units, S). In a rapidly growing bacterium, ribosomes may compose 1/4 the weight of the cell; because so many ribosomes are needed, multiple copies of the rRNA genes are found (130 copies in Drosophila).
The prokaryotic ribosome (70S) is composed of 2 subunits (30S subunit with 21 proteins and a 16S molecule of rRNA and a 50S subunit with 34 proteins, a 23S rRNA molecule, and a 5S molecule). The ribosomes of mitochondria and chloroplasts are distinct from those of the eukaryotic cytoplasm and resemble prokaryotic ribosomes. Eukaryotic ribosomes vary in size from 55S to 66S in animals to 70S to 80S in plants and fungi. The prokaryotic ribosome is 66% RNA, the eukaryotic ribosome is 60% RNA. In eukaryotes, the rRNA pieces are assembled with the ribosomal proteins (which have migrated into the nucleus) in the nucleolus; the area around which the nucleolus forms (the nucleolar organizer) contains the rRNA genes
Microsporidia are primitive eukaryotes and they possess a ribosome whose size is similar to that of prokaryotes. In all eukaryotic ribosomes, only those of microsporidia lack a 5.8 S subunit. The large subunit rRNA in microsporidia and prokaryotes is homologous to the 5.8S subunit at its 5’end (Vossbrink, 1986).
The role of rRNA molecules in ribosomes is essential. rRNA interacts with mRNA and tRNA at each step of translation. Mutations in rRNA can change the amino acid order of proteins and it seems that it is the rRNA of a ribosome, not the proteins, which perform peptidyl transferase function of joining amino acids in the growing protein. Notice the percentage of the ribosome which is composed of rRNA (blue) in the adjacent below.
Although the ribosome is large, codon recognition and peptidyl transferase involves small regions of the RNA (Gesteland, 1993).
rRNA In The Human Genome
There are an estimated 150-300 copies of rRNA genes in the human genome. Many of these genes exist in clusters (cluster 1 is located on chromosome 13, cluster 2 on chromosome 14, cluster 3 on chromosome 15, cluster 4 on chromosome 21, and cluster 5 on chromosome 22). Interestingly, the rRNA genes are located in region p12 of each of these chromosomes which all have satellite DNA.
rRNA1 makes a 45S precursor rRNA which is later cut to make the 18S, 5.8S, and 28S rRNAs. A separate gene codes for the 5S rRNA.
There are two rRNAs encoded by the mitochondrial genome: MTRNR1 (nucleotides 648-1601) and MTRNR2 (nucleotides 1671-32229). Variations of both of these rRNA genes can cause sensitivity to antibiotics in humans. This is understandable since many antibiotics function by acting on prokaryotic ribosomes and mitochondria descended from prokaryotic endosymbionts. Mutations in MTRNR1 can also cause deafness (OMIM).
THE MANY FAMILIES OF RIBOSOMAL PROTEINS
Ribosomes are the only organelles which
are conserved between all eukaryotic and prokaryotic organisms. As the sites of protein synthesis, they are
essential parts of the cell. In mammals, ribosomes are composed 4 types
of rRNA and around 80 different proteins. In mammalian cells, ribosomal proteins can compose
up to 15% of a cell’s total protein and 7-9% of the mRNAs which are made.
It seems that these proteins are expressed in about equal amounts
in cells. Some have been found
to be expressed at higher levels in cancer cells (but as genes which are
essential for growth, this may not be that significant an observation).
Most of these proteins are members of different multigene families (some exist only as a single copy in the human genome, such as RPL37A). Interestingly, although there are multiple copies of most of these ribosomal proteins, typically only one copy is functional and the others are all pseudogenes. The majority of the genes for these proteins lack the TATA and CAAT regions in their promoters which most genes have. The mRNAs of all vertebrate ribosomal proteins have a short 5’ untranslated region with 12 pyrimidines. The N terminus of the proteins is conserved.
Little is known about the majority of ribosomal proteins.
Below are images (views of two opposite sides) of the large subunit of a prokaryotic ribosome with the ribosomal proteins labelled.
Compared to bacteria, archaea and eukaryotes possess more ribosomal proteins which may indicate an increased selection for the regulation of translation (Karlin, 2005).
Below are images of individual ribosomal proteins isolated from bacteria.
Ribosomal Proteins of the Human Genome
RP27A—is part of a fusion protein with ubiquitin. Although the ribosomal protein is separated from ubiquitin when the fusion protein is processed, the ubiquitin seems to be required for its proper incorporation into the ribosome.
A fusion protein between RPL22 and the gene AML1 is found in some leukemias after a tranlsocation, but the protein may not be functional.
RPS6 is the major substrate of kinases in the ribosome. An increase in its expression is observed in proliferating cells and the inability to increase its expression may actually be involved in halting the cell cycle.
At least 2 ribosomal proteins, RPS3 and RPS3A, encode snoRNAs (small nucleolar RNAs) in their introns. RPS3A has 2 introns with 2 separate snoRNAs.
RPS3 can function as an endonuclease involved in the repair of ultraviolet light damage in addition to being a ribosomal protein.
Mutations in RPS19 are involved in Diamond Blackfan anemia which can cause problems as diverse as limb malformations and duplicated ureters. Mutations in RPL7 result in autoantigens involved in several autoimmune diseases, including lupus.
A pseudogene of RPL7 is located in the intron of a non-related gene, the FMS gene. A pseudogene of RPL38 is located in the gene for the receptor of angiotensin II.
At least 2 ribosomal proteins, PRL37 and RPS27, have zinc finger domains which bind nucleic acids.
RPL8 is part of the A site of the ribosome.
RPS4X and RPS4Y are located on the sex chromosomes. These two genes diverged before the last common ancestor of placental mammals and their proteins differ by 19 amino acids (--as a result, ribosomes in men and women differ in structure!). In men, both the X and Y genes are expressed. In women, both genes are expressed even though one of the genes is close to the inactivation center on the X chromosome. There is evidence that having only one copy of RPS4 (haploinsufficiency) is responsible for some of the symptoms of Turner syndrome women. Interestingly, men lacking the gene on the Y chromosome also display some of the symptoms associated with Turner syndrome women.
The nuclear genome also possesses 2 genes, MRPL12 and MRPS12, which encode ribosomal proteins used only in the mitochondria. These proteins are homologous to ribosomal proteins found in bacteria and were probably moved to the nucleus through lateral transfer.
THE RIBOSOME AND THE BIRTH OF MODERN CELLS
The ribosome should be viewed as a ribozyme—an RNA enzyme. No
translation factor (such as EF-G) is required for translation. It could have formed in precells
which depended primarily on functional RNA molecules but which had begun
to use amino acid chains, perhaps as ways of stabilizing RNA molecules
(Woese, 2001, Cech, 2000, Nissen, 2000). It is possible that the ribosome originally
functioned in the polymerization of RNA and was later modified to enable
translation. Analysis of the tRNA
binding sites of ribosomes suggest that they
might once have functioned in the polymerization of RNA molecules (
The last common ancestor of all modern life had most, but not all, of its translational machinery in the forms found in modern organisms. Some ribosomal proteins are found only in bacteria, others only in eukaryotes and archaea, and others only in eukaryotes. The origin of modern cells probably occurred with the establishment of the translational mechanisms were established (Woese, 2002). The earliest translation would have been much simpler and much more inaccurate. It could have produced short proteins or proteins whose precise amino acid content was less critical (Woese, 1998). Once this threshold was crossed, lateral transfer would have become less valuable to early cells because it would be unlikely to add to the existing translational mechanisms (Woese, 1998).