PDB IDs of these five fabs are BLV1H12: 4K3D BLV5B8: 4K3E A01: 5ILT B11: 5IHU and 5IJV. Disulfide bonds formed within the knob region are represented as sticks.
The β-ribbon stalk is colored red, the type I β-turn is colored magenta, and the three antiparallel β strands are colored yellow, green and blue, respectively. (C) “Stalk and knob” structures of the ultralong CDR H3s. Four cysteine residues encoded by the germline IGHD8-2 are highlighted yellow. Nucleotides within a codon that can be mutated to a cysteine-encoding codon with just a single nucleotide change are colored red, and corresponding amino acids encoded by these codons are also colored red. Potential AID-induced somatic hypermutation hotspot motifs (“RGYW”/“WRCY”) in bovine germline IGHD8-2 are boxed on both strands of the DNA sequence. (B) Sequence and potential diversity of the ultralong D H region. PDB IDs of these two fabs are Yvo: 2AGJ B11: 5IHU. Note the two long β strands that make up the stalk of the bovine ultralong CDR H3 and the disulfide-bonded knob domain at the top. Heavy chains are colored dark green and light chains are colored pale green. The CDR H3 of each antibody is highlighted in red. Crystal structures of Yvo, a typical human antibody (left), and B11, an ultralong bovine antibody (right). (A) Comparison of normal and ultralong CDR H3 antibody fab fragments. Structure and genetics of ultralong complementarity determining region (CDR) H3 cow antibodies. For these unusual ultralong CDR H3 bovine antibodies, it is likely that only CDR H3 binds antigen, while the other CDRs play a merely structural role ( 10, 11).įigure 1. In a significant departure from antibodies of most vertebrates, about 10% of the antibodies found in cows have an ultralong CDR H3 ranging from 40 to 70 amino acids in length ( 3– 9) (Figure 1A). In most species, the CDR H3 forms a simple loop structure, which is typically 8–16 amino acids long in humans. The third CDR of the HC (CDR H3) often forms the most significant contact with antigen, is longer than the other CDRs, and usually plays a prominent role in antigen binding. These CDRs usually form loops, and together, the six CDRs (three from the HC and three from the LC) form the antigen binding site of an antibody. The segments of the variable region that bind antigen are termed complementarity determining regions (CDRs), and each HC and LC contains three CDRs. HCs typically have one variable region and three or four constant regions, while LCs have one variable region and one constant region. The variable region binds antigen and the constant region dictates which downstream effects will occur, such as activation of complement or the recruitment of macrophages, neutrophils, mast cells, basophils, cytotoxic T cells, or natural killer cells. Both HCs and LCs are composed of variable and constant regions. In most vertebrates, these HCs can pair with two different classes of LCs: lambda (λ) and kappa (κ). There are five classes of HC, each with a distinct function: IgM, IgD, IgG, IgA, and IgE. A typical antibody is composed of two heavy chains (HC) and two light chains (LC) bound together through both non-covalent interactions and disulfide bonds. They act by binding and inhibiting foreign substances in the body, such as viruses and bacteria, and then destroying them through complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, or antibody-dependent cellular phagocytosis ( 1, 2). In this review, we discuss the genetics, structures, and diversity of bovine ultralong antibodies, as well as the role of AID in creating a diverse antibody repertoire.Īntibodies, also known as immunoglobulins (Ig), are an essential and defining characteristic of the vertebrate immune system. Due to limited use of variable and diversity genes in the V(D)J recombination events that produce ultralong CDR H3 antibodies in cows, the diversity in the bovine ultralong antibody repertoire has been proposed to rely on AID-induced mutations targeted to the IGHD8-2 gene that encodes the entire knob region. Activation-induced cytidine deaminase (AID) has a proven role in diversifying antibody repertoires in humoral immunity, and it has been found to induce somatic hypermutation in bovine immunoglobulin genes both before and after contact with antigen. However, cows possess a subset of antibodies with ultralong CDR H3s that can range up to 70 amino acids and form a unique “stalk and knob” structure, with the knob protruding far out of the antibody surface, where it has the potential to bind antigens with concave epitopes. Typical antibodies found in humans and mice usually have short CDR H3s and generally flat binding surfaces. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States.
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