1蛋白质高级结构作用力

§2.4 蛋白质的结构和功能（续） §2.5 维持蛋白质高级结构的作用力
1, Complementary Interactions between Proteins and Ligands:
The Immune System and Immunoglobulins
2, Forces to stabilize the protein 3-D structure 3, protein structure prediction

1, Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins “Structural Immunology”

When a foreign substance - a virus, a bacterium, or even a foreign protein-invades the tissues of a higher vertebrate(脊椎动物) (like a human), the organism defends itself by what is called the immune response (免疫应答，免疫反应). The immune response is a first line of defense against infection and probably against cancer cells as well.

The immune response has two facets(形式): 1. Humoral immune response (体液免疫应答)Lymphatic cells(淋巴细胞) called B lymphocytes synthesize specific immunoglobulin(免疫球蛋白) molecules that are excreted(分泌) from the cell and bind to the invading substance. Binding either precipitates the foreign substance or marks it for destruction by cells called macrophages(巨噬细胞). 2. Cellular immune response (细胞免疫应答) Lymphatic cells called T lymphocytes, bearing immunoglobulin-like molecules on their surfaces, recognize and kill foreign or aberrant(异常的) cells.

Antigens and Antibodies: The foreign substance that elicits(引起) an immune response is called the antigen(抗原). A specific immunoglobulin that binds to the antigen is called the antibody(抗体). If the invading particle is large, like a cell, a virus, or a protein, many different antibodies may be elicited, each type binding specifically to an antigenic determinant (or epitope, 抗原决定簇) on the surface of the particle.

Immunoglobulin Structure – Each immunoglobulin monomer consists of four chains, two heavy chains (M = 53,000 each) and two light chains (M = 23,000 each), held together by disulfide bonds. In each chain are constant domains (identical in all antibodies of a given class) and a variable domain. Variations in the amino acid sequence (and therefore the tertiary structure) of the variable domains of the light and heavy chains confer(赋予) the multitudinous(多种多样的) specificities of antigens to different determinants.

Precipitating Antigens - A large protein, a virus, or a bacterial cell has many different potential antigenic determinants on its surface that antibody molecules can bind, thereby precipitating the antigen. Antigens with only one determinant, will bind to an antibody, but not precipitate. Precipitation also requires the antibody to be bivalent (to have two binding sites).

By careful proteolysis(蛋白酶水解), it is possible to cleave antibodies at the hinge region to produce Fab fragments with only one binding site each. Such fragments will bind, but not precipitate antigen.

Schematic models of an antibody molecule and a Fab fragment

Humans have five classes of immunoglobulins

Model of the IgG from X-ray diffraction studies
(b) A ribbon model of the first complete IgG molecule to be crystallized and structurally analyzed (PDB ID 1IGT). Although the molecule contains two identical heavy chains (two shades of blue) and two identical light chains (two shades of red), it crystallized in the asymmetric conformation shown. Conformational flexibility may be important to the function of immunoglobulins.

Signaling Macrophages – The constant domains of the heavy chains in the base of the Y-shaped immunoglobulin molecule hold the chains together and function as effectors, to signal macrophages in the circulatory system(循环系统) to attack particles or cells that have been labeled by antibody binding. Macrophages are large white blood cells that are specially adapted to engulf(吞噬) and digest foreign particles. Differences in heavy chains identify immunoglobulin types for delivery to different tissues or for secretion.

Phagocytosis(吞噬作用) of an antibody-bound virus by a macrophage. The Fc regions of the antibodies bind to Fc receptors on the surface of the macrophage, triggering(触发) the macrophage to engulf and destroy the virus

Induced fit

The immune response is incredibly versatile(通用的) 1. It can respond to an enormous number of different foreign substances. （广谱性） 2. The immune response has a so-called memory: After an initial exposure to a given antigen, a second exposure at a later date results in rapid and much more massive production of the antibodies specific to the antigen. （免疫记忆）

Antigenic determinants (抗原决定簇)

Clonal Selection Theory – The clonal selection theory explains how the body has an inherent(天生的) ability to produce an immense diversity of antibodies with different amino acid sequences that are able to bind an enormous range of antigens.
The theory that the mutation of stem cells produces all possible templates for antibody production and that exposure to a specific antigen selectively stimulates the proliferation of the cell with the appropriate template to form a clone or colony of specific antibody-forming cells.

The clonal selection theory of the immune response
1. B cell precursors randomly rearrange variable coding parts of antibody genes. Afterwards, antigen binds to a clone with specific membrane antibody, resulting in differentiation to antibody secreting plasma cells. 2. The antigen causes a nonspecific clone of B lymphocytes to proliferate and secrete antibody molecules capable of binding to any foreign antigen. 3. Antigen causes the growth of a clone of lymphocytes which then rearrange DNA, creating a gene coding for a specific antibody 4. A clone of macrophages with specific receptor for antigen phagocytoses antigen, then rearranges DNA to generate specific antibody-coding genes.

Generation of Antibody Diversity Sequence Shuffling/Changes - The human genome simply does not have enough room to encode a separate gene for each of the millions of different immunoglobulin molecules occurring in B stem cells. Instead, the following two special processes occur in these cells.

1. Recombination of Exons - The major source of antibody diversity is recombination of exons. The genomes of higher vertebrates contain "libraries" of exons corresponding to different portions of the immunoglobulin molecule and mechanisms for rearranging these exons to create different combinations in both the heavy and light chains. Shuffling of these exons occurs in B cells and creates new immunoglobulins in individual cells.