Protein synthesis is extremely important to cells, and so large numbers of ribosomes are found throughout cells (often numbering in the hundreds or thousands). Ribosomes exist floating freely in the cytoplasm, and also bound to the endoplasmic reticulum (ER). ER bound to ribosomes is called rough ER because the ribosomes appear as black dots on the ER giving it a rough texture. These organelles are quite small, made up of 50 proteins and several long RNAs intricately bound together.

Below is an image that shows a ribosome, shown in white and cyan, controlling a red package of transfer RNA, which deposits an amino acid building block onto the yellow protein being created. The ribosome chooses the appropriate amino acid based on information stored in the green strand of RNA.

The Tunnel and the Donut

The code is translated on Ribosomes. These ribosomes provide the structural site where the mRNA sits. The amino acids for the proteins are carried to the site by tRNA (transfer RNA). In the second color cartoon below, these are shown as blue molecules. Each transfer RNA (tRNA) has a nucleotide triplet which binds to the complementary sequence on the mRNA (see the three letters at the bottom of each molecule.)

The illustration below shows the basic sequence of transcription and translational events.

A more colorful illustration of protein synthesis.

The translation of DNA/RNA instructions and the synthesis of proteins is arguably the most complex single-site operation carried out by biological systems at the molecular level, so as you can see, the ribosome has a huge molecular role!

In the past, the ribosome was thought of as an important but passive machine in the synthesis of proteins while studies now suggests that it plays a more active role in maintaining proper cellular function.

The most common cause of Ribosome malfunction is related to ALZHEIMER'S DISEASE.

Alzheimer's disease (AD) is a progressive and devastating disorder that is often preceded by mild cognitive impairment (MCI). In the present study, we report that in multiple cortical areas of MCI and AD subjects, there is a significant impairment in ribosome function that is not observed in the cerebellum of the same subjects. The impairment in ribosome function is associated with a decreased rate and capacity for protein synthesis, decreased ribosomal RNA and tRNA levels, and increased RNA oxidation. No alteration in the level of initiation factors was observed in the brain regions exhibiting impairments in protein synthesis. Together, these data indicate for the first time that impairments in protein synthesis may be one of the earliest neurochemical alterations in AD and directly demonstrate that the polyribosome complex is adversely affected early in the development of AD. These data have important implications for AD studies involving proteomics and studies analyzing proteolysis in AD, indicate that oxidative damage may contribute to decreased protein synthesis, and suggest a role for alterations in protein synthesis as a novel contributor to the onset and development of AD.

Ribosome dysfunction has also been found to lead to CANCER.

Davide Ruggero, Ph.D., of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering was the first author of a study that showed that a defect in ribosome function may cause cancer.

Here is an interesting excerpt of his findings:
New York, January 10, 2003 -- A rare genetic syndrome, Dyskeratosis Congenita (DC), may hold the key to understanding a mechanism that causes premature aging and cancer. Recreating DC in genetically altered knockout mice, researchers at Memorial Sloan-Kettering Cancer Center and colleagues proved that the disorder was caused, as theorized, by mutations in the DKC1 gene. Unexpectedly, they also showed that DC was caused by a disruption in ribosome function and not due to shortened telomeres (the distal end of a chromosome arm) as previously hypothesized. Their results, published in the January 10 issue of Science, may have implications for development of drugs that kill cancer cells by specifically targeting ribosomes, similar to the way ribosome targets have been key to the development of antibiotics for specific bacterial infections.

To read the article in it's entirety, go to: http://www.mskcc.org/mskcc/html/12318.cfm

Ribosome dysfunction is also related to ANTIOBIOTIC RESISTANCE.

The new structural data indicate that the L22 mutation increases the size of a "tunnel" in the ribosome, through which the growing peptide chain moves during synthesis. This tunnel is normally blocked by macrolide antibiotics. In the mutant form, the tunnel widens, which may explain why macrolide antibiotics are no longer effective. You can see in the "Tunnel and Donut" illustration above where exactly on the ribosome widens.

Insights about the ribosomal origins of antibiotic resistance are already being applied to the development of new antibiotics. One company leading the way is Rib-X Pharmaceuticals, which was founded by Steitz and colleagues at Yale. "About half of current antibiotics target the ribosome, and most of them target the large subunit," he said. "So, such advances have the potential for significant clinical impact. The general strategy of Rib-X to overcome resistance is to create new hybrid antibiotics that possess the ability to bind to interact simultaneously with different, nearby sites on the ribosome represented by different classes of antibiotics.

In a landmark achievement, Yale researchers have determined the atomic structure of the ribosome's large subunit, paving the way for more effective drugs to fight infection!

Another couple of cool articles on Antibiotic Resistance. To read them in their entirety go to: http://www.yale.edu/opa/v29.n1/story3.htm
Researchers make gains in understanding antibiotic resistance: http://www.medicalnewstoday.com/medicalnews.php?newsid=23255

Ribosome dysfunction can also lead to a very rare disease called SHWACHMAN-DIAMOND SYNDROME.

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. This syndrome shows a wide range of abnormalities and symptoms.

The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormalities and growth retardation. Neutropenia may be intermittent or persistent and is the most common haematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia. Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients. More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients), and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographs from 15 patients indicated that all of them had at least one skeletal anomaly, though many were sub-clinical.

Three more diseases that may also be linked to defective ribosome function:
Diamond-Blackfan anemia, X-linked dyskeratosis congenita, and cartilage-hair hypoplasia.

Dyskeratosis Congenita is an extremely rare, fatal X-linked recessive disease that results in premature aging, severe anemia due to bone marrow failure, and dyskeratosis of the nails, skin hyperpigmentation, and cancer. It is caused by mutations in the DKC1 gene that encodes a protein named dyskerin, which is widely distributed in tissues. Dyskerin is thought to be involved in the regulation of ribosomal function and interacts with the RNA component of telomerase, which is essential in the regulation of telomere length. Patients with DC have in fact, unusually shortened telomeres, which was hypothesized to cause the various features of the disease including genomic instability and, in turn, cancer susceptibility.

In Blackfan Diamond Anemia(or Diamond Blackfan) anemia the body's bone marrow produces little or no red blood cells. A person is born with it. It affects approximately 600 - 700 people worldwide. Its cause is unknown, although a genetic error on Chromosome 19 is associated with about 25% of cases. In about 10-20% of cases, there is a family history of the disorder.

What are the symptoms? - Blackfan Diamond anemia can be difficult to identify. In about one-third of children born with the disorder there are physical defects such as hand deformities or heart defects, but a clear set of signs hasn't been identified. The symptoms may also vary greatly, from very mild to severe and life-threatening.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive inherited disorder that results in short-limb dwarfism and is predominantly associated with a T-cell immunodeficiency. CHH and other short-limb dwarfism phenotypes are associated with metaphyseal or spondyloepiphyseal dysplasia. CHH is a variant of short-limb dwarfism in which fine sparse hair is also present. The immunodeficiency in CHH is either an isolated T-cell or combined T- and B-cell immunodeficiency.

If you are interested in learning more about these diseases and how to help, here are some websites you can look at.>

The American Association For Cancer Research http://www.aacr.org/
Alzheimer's Disease http://www.alz.org/
Alzheimer's Disease http://www.alzfdn.org/
Alzheimer's Disease http://www.visitingangels.com/alzheimersinfo.htm
Shwachman Diamond Disease http://www.shwachman-diamond.org/
Shwachman Diamond Disease http://www.shwachman.org/