I. Receptors.

II. Transport proteins.

III. Protein hormones.

IV. Structural proteins.

V. Transcription factors.

Terms.

Erratum Page 251, last sentence, should read, "The average life of human red blood cells is ca. 120 days."

I. Receptor proteins are proteins that bind other cell components, as a result of which some function can occur. Many are found in cell membranes and are involved in transport of components or signals across the membrane. Others function as transcription factors (see V below). Receptors may function less effectively as a result of mutations in the genes that code for them. Defects may be dominant or recessive, depending on how many copies of the functional protein are needed to produce the normal wild-type phenotype.

A. Defects in the androgen (testosterone) receptor (AR) were discussed in Lecture 11.
1. The AR occurs in the cytoplasm, where it can bind to testosterone or dihydrotestosterone. These complexes migrate to the nucleus, where they regulate transcription of target genes.

2. Persons with complete lack of AR activity have androgen insensitivity (testicular feminization). Heterozygous females are normal.

3. Males with a partially functional AR are intersexes, with development that is primarily male or female, depending on the degree of defect in the receptor.

B. Defects in the LDL receptor (low-density lipoprotein receptor) interfere with cholesterol uptake from the bloodstream, which in turn causes excess cholesterol synthesis in the liver and high levels of blood cholesterol.
1. The LDL receptor is located in the cell membrane, where it binds plasma LDL and transports it into the cell interior. This occurs primarily in the liver.

2. Defective LDL receptor function is a "dominant" trait, but homozygotes are much more severely affected.

3. Ca. 1 in 500 persons is heterozygous, with very high blood cholesterol and risk of early coronary disease. This condition is known as familial hypercholesterolemia.

4. There are several medications now available that interfere with cholesterol synthesis, thereby lowering the risk of heart disease.

5. Many different mutations are known. In some, no receptors are made. In others, receptors are made but are defective in various functions, e.g. (a) the receptors will not anchor in the cell membrane, (b) the receptors anchor but cannot bind LDL, or (c) LDL is bound but the receptors cannot move to the interior of the cell.

A. The most obvious transport protein in higher animals is hemoglobin, which transports oxygen from the lungs to the tissues where it is needed.
1. Hb is a tetramer, i.e. there are four polypeptide subunits. Two of the subunits are identical and are designated alpha globin; the other two are also identical to each other and are called beta globin.

2. The alpha chains are coded by genes on chromosome 16 and the beta chains are coded on chromosome 11. Each is a member of a cluster of similar genes that function at different times during embryonic and fetal development.

B. Hundreds of variant forms of hemoglobins are known, most of which are very rare. However, some are common (polymorphic) in certain populations.
1. Sickle cell hemoglobin (HbS) results from a single nucleotide substitution in the gene that codes for the beta globin chain. It transports oxygen very well, but in tissues in which oxygen is low, Hb S tends to form a crystalline-like structure that causes interruption of circulation and that also causes the red cells to rupture. Persons who are homozygous for HbS have sickle cell anemia and rarely survive the teenage years. Persons who are heterozygous have both HbS and HbA (normal) in their red cells and are said to have sickle cell trait. They are phenotypically normal.

2. Most of the difficulty with abnormal hemoglobins is that synthesis is too low to satisfy needs. Therefore affected persons have anemia. In some instances, a Hb gene may be deleted entirely, causing more severe anemia. The general term for inherited anemias due to variant Hb genes is thalassemia.

[Note: The textbook goes into considerable detail on Hb variants. Students will not be expected to recall these details.]

A. Hormones are substances secreted by a tissue or organ into the bloodstream and whose function is to regulate other organs and tissues.

B. Protein hormones typically bind to specific receptors in the cell membrane, where they trigger a signal that alters cell activity.

C. Among the hormones for which mutant forms are known is growth hormone, secreted into the blood stream by the pituitary gland. Persons who are homozygous for nonfunctional GH genes are dwarfs.

[Note: The textbook doesn't mention protein hormones. However, students should know about them.]

A. One example is elliptocytosis, a dominant disorder that results from alteration of a structural protein that lies under the surface of red cell membranes.

B. Marfan syndrome is often due to structural alteration of fibrillin, a protein that is an important component of connective tissue. Defects in fibrillin cause the connective tissue to be weak. Abraham Lincoln is thought to have had this dominant disorder.

C. Collagen is the major substance that occurs outside our cells and that holds cells together, allowing us to be multicellular. About a dozen types of collagen are known, each composed of three polypeptide chains (2 of one type and one of a second type. Each different polypeptide is coded by a different gene. In addition to occasional variations in the collagen structural genes, there can be modifications of other genes whose products modify collagen polypeptides before they are incorporated into fibrils. Many of the collagen mutations produce some form of osteogenesis imperfecta, characterized by brittle bones, often accompanied by deafness and blue sclerae.

A. Transcription factors often have one of several structural motifs that indicate DNA binding. A common motif is a pattern of amino acids that bind zinc, forming structures known as zinc fingers. Often the presence of these motifs is the only direct evidence that the proteins function as transcription factors. An example is one of the mutations that cause xeroderma pigmentosum, a rare recessive trait whose phenotype is the inability to repair certain types of gene mutations.

B. Variant forms of transcription factors are rare. If such occurred, it would probably cause aberrant transcription of all the genes regulated by that factor and would most likely be a lethal condition. Variants are known in somatic cells in cancer; these will be discussed further under that topic. The SRY gene product, the androgen receptor, and the estrogen receptor are examples of transcription factors in which defects are known, presumably because their function is in sexual development and not in more basic processes on which cell survival depends. As is indicated by these examples, receptor proteins may also be transcription factors, though most probably are not.

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