Archive for January, 2011

Somatic Recombination: Part 2, Transmembrane Receptors

by on Jan.07, 2011, under Immunology

The ability of a cell to sense its environment and receive information from other cells is central to the health and function of virtually every cell in the human body.  The information obtained by a cell at its surface will induce signals within the cytoplasm that end in a variety of effects including cell motility (movement), maturation, and even death.  Contrary to the static picture of cells, save neurons, from the biology texts of my youth, cells are dynamic and interactive. Further, this interactivity is critical not only to the health of the cell but the organism as well.  Errors in intracellular signaling have been shown to play a role in cancer as well as many other conditions.

The primary implement for this environmental sensing and intercellular communication is the transmembrane receptor.  They are so named because they reside within the cell membrane and extend into the cytoplasm on one end and the extra cellular fluid on the other.  There are many different types of these receptors that can bind to a wide range of molecules (ligands).  They are classified into families with different binding specificities and signaling effects.  For example, chemotactic receptors induce the mechanisms of cellular motion.  Members of this receptor family can be found in many places including cells of the Innate and Adaptive Immune System.  The Neutrophil, the most important cell type in the Innate, possess several different chemotactic receptors in its membrane which drive changes in the cytoarchitecture.  In the video below, a Neutrophil can be seen pursuing a bacterium by following a chemical trail produced in its wake utilizing it’s chemotactic receptors.  Amazingly, this video was taken in real time.

All transmembrane receptors in the families I’ve encountered in my reading bind to specific patterns of amino acids within a peptide or complete protein or a combination of protein and sugar or fat.  This is referred to as the binding specificity of the receptor and it varies in strength (avidity) with minor variations in the amino acid sequence of the binding target.

As far as I’ve read, a given receptor or receptor family is rarely unique to a one species.  All receptors of a given type will bind to a very similar, if not the exact same, amino acid pattern regardless of whether the receptor is on a human Neutrophil or a staphylococcus bacterium.  One interesting example is the family of so called Toll receptors which are highly important to immune system function.  These receptors are conserved throughout evolution and can be found in both vertebrates and invertebrates alike 1.  Another fact that makes the Toll receptors so interesting to me is that early on in the development of the fruit fly a toll receptor is critical for establishing the “top and bottom” orientation of the embryo.

The transmembrane receptors we are interested in here are called antigen receptors, further, in context of a B cell; Immunoglobulins.  Immunoglobulins stand out for two reasons.  First, they have two possible fates.  Once assembled, some Immunoglobulins will be transported to and embedded in the B cell membrane where they function as antigen receptors.  However, after assembly, they can also be secreted by the B cell as antibodies and enter the circulatory system.  Antibodies often encounter their binding targets, or ligands, in proteins found covering the surface of a pathogen such as a bacterium.  By binding in large numbers, the antibodies essentially coat, or opsonize the bacterium, thus marking the pathogen and making more efficient the action of cells in the innate immune system.  These cells, such as Neutrophils, have transmembrane receptors known as Fc receptors that bind to the ends of antibody molecules at what is known as their Constant Region.  This region is so named because it is always constructed by the same amino acid sequence.

The second reason immunoglobulins stand out can be found at the other end of the antibody molecule opposite the Constant Region which is called the Variable Region.  In contrast to the Constant Region, and any region of any other receptor I’ve read about, the amino acid sequence that makes up this region is almost infinitely variable.  This is the region that makes immunoglobulins, whether secreted as antibodies or stuck in the membrane as antigen receptors, immensely useful in protecting the body from pathogen invaders.  This is because every amino acid sequence found in every possible invader, existing as well as yet to evolve, need not be encoded into the genome for transcription as the binding site sequence of an Immunoglobulin.   This would require more genes than there are in the entire genome; another process must be employed to produce the sequences of the Variable Regions.

Immunoglobulins are generated dynamically during the cell’s development, with virtually infinite potential for diversity in binding specificity.  Therefore, the receptors and antibodies of each new B cell will have specificity to a different peptide because each one bears receptors that are specific for a different sequence of amino acids.  The process responsible for this dynamic specificity is called Somatic Recombination, and I will present it over my next two posts.

Read my Health Science Disclaimer

  1. Toll and Toll-like receptors in Drosophila
    H. Bilak, S. Tauszig-Delamasure and J.-L. Imler1
    UPR9022 CNRS, 15 rue Rene´ Descartes, 67084 Strasbourg Cedex, France
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