The Complement Facts: Book PDF
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C 11NH C1 inhibitor C4BP C4b-binding protein CRD carbohydrate-recognition domain CRP C-reactive protein DAF decay-accelerating factor VBE Epstein-Barr virus EGF epidermal growth factor FGF fibroblast growth factor fMLP formyl-methionyl-leucyl-phenylalanine GPI glycosylphosphatidylinositol HIV human immunodeficiency virus IFNy interferon y Ig immunoglobulin 1-LI interleukin 1 LAD leukocyte adhesion deficiency LPS lipopolysaccharide MAC membrane attack complex MBL mannose-binding lectin MCP membrane cofactor protein MHC major histocompatibility complex MIDAS metal ion-dependant adhesion site Mr )K( relative molecular mass NK natural killer PDGF platelet-derived growth factor PMA phorbol myristate acetate PMN polymorphonuclear leukocyte PTK protein tyrosine kinase RaRF Ra-reactive factor RFLP restriction fragment length polymorphism SAP serum amyloid protein SDS-PAGE polyacrylamide gel electrophoresis in sodium dodecyl sulfate ELS systemic lupus erythematosus TGF3 transforming growth factor fl TNFa tumour necrosis factor a VNTR variable number tandem repeat VWF von Willebrand factor vii The authors wish to thank all those who contributed entries for this volume and for their comments and suggestions. In addition, we are indebted to a number of contributors for additional information they provided. Dr Robert Sim for Figure 2 in Chapter 2, Dr David Isenman for the C3 and C4 catabolism diagrams and Dr Robert Ames for the C3a and C5a receptor diagrams. We would also like to thank Dr James Sodetz for advice on nomenclature, and Dr Alex Law for providing much of the information used in the CR3 chapter on deficiency and polymorphism, including unpublished data. We would like to thank Dr Robert Sim for critical reading of the introduction and Jane Rose for prolific proofreading. Finally, we would like to thank Dr Lilian Leung for her encouragement in the final stages of the preparation of this book. The field of complement is rapidly changing with the constant addition of new data. In light of this, we would be grateful if readers could point out any errors, omissions or indeed new information which could then be incorporated into future editions of this book. Please send these to the Editor, The Complement FactsBook, Academic Press, 24-28 Oval Road, London NW1 7DX, UK. Bernard .J Morley Mark .J Walport °°° Vlll AIMS AND SCOPE OF THE BOOK The aim of this book is to present concise biochemical information about the proteins of the complement system. A novel aspect of this book compared with others in the FactsBook series is the inclusion of cDNA structure and intron-exon boundary details. This enables the design of primers for DNA amplification by the polymerase chain reaction, facilitating both functional mutation studies and the design of probes for expression work. The focus of the book is on the human system, though accession numbers have been included for other species. In the case of conglutinin, where no human homologue has been identified, the bovine molecule has been described. The complement proteins are largely built up from protein modules and it is therefore quite easy to divide them into families of structurally related molecules. This is the basis for the separate chapters. A few proteins escape such simple classification (C1 inhibitor, apolipoprotein J (clusterin), properdin and CD59) and these have been grouped together in a separate chapter. ORGANIZATION OF THE DATA Entries are classified into the following sections, each of which is briefly described. Other names Entries are identified by the accepted nomenclature for the complement system as described .2,1 More recently characterized components are entered under their most commonly used name. Historically, many of the complement proteins have been known by alternative names, or were identified as members of other protein families. Hence different researchers may know them by different designations. All of these alternatives have been included. Physicochemical properties This section includes data on the number of amino acids in the mature protein and leader peptide (if present); the pI; the molecular weight, both observed under reduced and non-reduced conditions, and predicted based on amino acid composition; the number and location of putative N-glycosylation sites, and if known, whether the sites are occupied; and the number and location of interchain disulfide bonds. Intrachain disulfide bonds are not listed, nor are O-linked glycosylation sites, though the latter are mentioned in the structure section. Structure Details of the three-dimensional structure where known are included in this section together with any other significant features. Function The mechanism of activation of the molecule is detailed in this section, together with a brief description of its role in the complement pathway. Other functional activity, outside the complement pathway is also mentioned. The modular structure of each protein is illustrated and the functional importance of each Ii Table 1. Key to the schematic diagrams. All diagrams show modules to scale, with the key illustrating average sizes. SYMBOL PROTEIN MODULE ABBREVIATION O Complement control protein repeat CCP Serine protease domain Factor I/membrane attack complex C6/7 module FIMAC 0 Epidermal growth factor-like repeat EGF t Ga 2. Calcium-binding epidermal growth factor-like Ca *~ EGF repeat llllIIIIIIIIIIIII Von Willebrand factor type A VWFA Thrombospondin type 1 repeat TSP1 Low density lipoprotein receptor class A repeat LDLRA CUB domain (first identified in Clr/Cls, uEGF, CUB bone morphogenic protein) Membrane attack complex proteins/perforin-like MACPF segment Collagen-like domain I I O Carbohydrate-recognition domain CRD t Alpha-helical coiled-coil "neck" region Serine, threonine, proline-rich mucin-like domain STP | Cytoplasmic domain 8 Transmembrane domain ( for C3aR and CSaR) -- Glycosylphosphatidylinositol anchor GPI anchor I ICZ~ Other domains (see individual sections) I I Scale: 200 amino acids module noted. A key for the common protein modules is provided in Table ,1 together with their full names and the abbreviations 3 used throughout the text. Modules which are only present in a single protein in this book, are indicated by a white box and the nature of that module is indicated in the protein modules II section of the particular entry. For non-modular proteins such as the C3a and C5a receptors, a diagram has been included only if this helps to illustrate important structural features. In the case of C3 and C4, a diagram has been included to show the degradation pathways of these proteins since this is pertinent to their function. Tissue distribution For the secreted proteins, the typical serum concentration is provided and other biological fluids known to contain the protein are indicated. The primary site of synthesis is given, together with secondary sites. These are not meant to be exhaustive lists of cells expressing a given protein. In many cases, C3 for example, a large number of cell types have been assayed for expression. However, the absence of a cell or tissue from the list should not be taken as evidence that there is no expression from that cell type. For cell surface proteins, cell types which have been clearly demonstrated to express the molecule are listed. Regulation of expression Stimuli which alter protein expression are described. Mechanisms, if known, are detailed. Protein sequence The sequence is shown in the single letter amino acid code. Numbering starts with the initiator methionine residue. The leader sequence is underlined, as are cleavage sites between chains and any special features of specific molecules, for example the residues which form the thioester bond in C3/C4 and the transmembrane domains of the C3a and C5a receptors. Putative and known N-linked glycosylated sites are indicated by N. Sites known not to be occupied are not indicated. Protein modules For the protein modules listed in Table ,1 the leader sequence and some important binding regions, the amino acid boundaries and exons are indicated. For C3 and C4, the thioester domain is indicated, while for the serine proteases, the position of the catalytic triad of the active site (H-D-S) is listed. Chromosomal location The chromosomal location of the gene in both human and mouse, where known, is given. Closely linked genes are also indicated. cDNA sequence The cDNA sequence is given. Where known, the sequence starts with the 5' end of the message. Otherwise, the most 5' sequence is given. All possible exons are included in the sequence. Where alternative splicing removes an exon from the mature message, this is noted. The initiation codon, termination codon and the putative polyadenylation signals are all indicated. In addition, exon-intron boundaries are shown by underlining the first five nucleotides in each exon. No II Introduction intronic sequences are included. Where there are discrepancies in published sequences, these are indicated. Genomic structure Where the structure of the human gene is known (with the exception of conglutinin, for which the bovine gene structure is given), this is drawn to scale. The gene is represented by a single horizontal line while the exons are indicated by vertical bars, also to scale. Only the first and last exons are numbered, together with a central exon for the larger genes. Accession numbers Only the GenBank/EMBL accession numbers are included. These are listed as cDNA or genomic depending on the sequences they contain. Deficiency The mode of inheritance of deficiency in humans is stated together with the functional effects of deficiency and any clinical correlates. The molecular basis is stated, for example in factor I: A1282 to T, H418 to L; three chromosomes/patients/families where A is the normal nucleotide 1282 is the position in the presented cDNA sequence T is the mutant nucleotide H is the normal amino acid 418 is the position in the presented protein sequence L is the mutant, non- or aberrantly functional amino acid and 'three chromosomes/patients/families' represents the number of times this mutation has been described. Polymorphic variants Polymorphic variants at the protein level, at the level of restriction fragment length polymorphisms (RFLPs) or where the molecular basis is fully described are listed. Alleles are named A/B where A is the nucleotide/amino acid to the left of the numbering. References A fully comprehensive list of references is not compatible with the format. However, each entry includes the major references, while key references are highlighted in bold. These represent either important work in the field or key reviews which will link to further references. secnerefeR i World Health Organization. (1968) Bull. WHO 39, 935-938. 2 IUIS-WHO Nomenclature Committee (1981) .J Immunol. 127, 1261-1262. 3 Bork, P. and Bairoch, A. (1995)Trends Biochem. Sci. 20, Suppl. March C03. m 2 The Complement System HISTORICAL PERSPECTIVE In the late nineteenth century, much scientific interest was focused on the mechanisms involved in protecting the body from attack by microorganisms. Two apparently contradictory theories of bacteriolysis emerged during this time. The first, the ''cellular theory'', stemmed from the work of Elie Metchnikoff who demonstrated the existence of blood cells which could ingest invading bacteria. The second, the "humoral theory" of bacteriolysis, was based on work from Fodor, Nuttall and Buchner who identified a heat-labile component of fresh, cell-free serum which was capable of bacteriolysis^. Buchner termed this activity "alexin", from the Greek "without a name". In 1894, Pfeiffer observed that cholera vibrios injected into the peritoneum of immune guinea pigs were lysed^. Towards the end of the nineteenth century, Bordet working at the Pasteur Institute, extended this work by demonstrating that serum from immune animals lost its lytic activity after heating but that activity could be fully restored by the addition of non-immune serum. Bordet surmised that two factors were involved, one of which was heat-labile and the other was a stable substance present in immune serum^. The former he assumed was alexin while the latter he termed the "sensitizer". Meanwhile, Ehrlich and Morgenroth, examining erythrocyte haemolysis by immune serum, confirmed the idea that two "principles" were required for lysis. The first principle, which was present in a thermostable form in immune serum, they termed "amboreceptors" or "immune bodies". The second, a heat-labile substance present in the "body juices", they called "complement" due to the fact that it "complemented" the activity of the amboreceptors. However, it was Bordet and Gengou who described the first complement fixation test, thereby establishing the quantitative role played by complement in cell lysis and dispelling the idea that it was merely an accessory factor as implied by Ehrlich's name. For this reason, Bordet is generally credited with the discovery of the complement system. In the absence of robust biochemical techniques, elucidation of the proteinaceous nature of complement and of the multiple components proceeded fairly slowly over the next 40 years. However, by the late 1920s due to the work of Ferrata initially, and Coca and Gordon subsequently, four individual components were recognized. By 1941, Pillemer and co-workers had confirmed the proteinaceous nature of complement^. During the 1960s, Nelson characterized at least six components from guinea pig serum that were necessary for haemolytic activity^, while Miiller- Eberhard and colleagues focused on the purification and characterization of each of these components^. Also in the 1960s, Ueno and later Mayer used a reconstitution assay, adding partially purified components to antibody-sensitized sheep red blood cells, to unravel the reaction sequence of the classical pathway. The identification of the alternative pathway involved many of the same investigators in another complex challenge. Pillemer described the depletion of C3 from serum by zymosan in the absence of any effect on CI, C2 and C4 levels in 1953. He also identified properdin as an activating factor in what he termed the properdin pathway^. Nelson offered an alternative explanation for these data in 1958*. He proposed that the properdin system was actually the classical pathway, but activated via antibodies to zymosan. In 1971, Miiller-Eberhard purified C3 proactivator and proposed the C3 activator system as an alternative method of complement activation^, thus supporting Pillemer's original hypothesis. The Complement System MODULAR STRUCTURE OF COMPONENTS The cloning and sequencing of the complement components in the last 20 years has augmented the extensive protein sequence already in existence and enabled protein structures to be identified. This has revealed the modular nature of the complement proteins and allowed their classification into five functional groups based on common structural motifs. Clq and the coUectins (Figure 1) SP-D I_J4^^^ SP-A C1q chains Conglutinin MBL Figure 1. Modular structure of Clq and the coUectins. See Table 1 for key. Additional domains are the globular region for Clq fCI^J; ^^<^ for conglutinin and MBL, the N-terminal cysteine-rich region f[]j. The structure of Clq is unusual and was originally described^^, supported by electron micrographs, as resembling a ''bunch of tulips''. Clq has 18 subunit chains formed into collagen-like triple helices with globular heads, through which Clq interacts with immunoglobulin. The serum lectin molecules, MBL and conglutinin, together with the lung surfactant proteins, SP-A and SP-D, share a marked similarity to Clq. They also have 12-18 polypeptide chains organized into the collagen-like domain with a globular C-terminus; however, in contrast to Clq, the globular domains of the coUectins bind a range of sugar moieties (Figure 2). Serine proteases (Figure 3) The enzymes of the complement system are serine proteases of the chymotrypsin family and trypsin subfamily. The distinguishing feature of this group is the serine protease domain containing the catalytic triad of histidine, aspartic acid and serine^^ The remaining domains of the enzymes such as the CCPs of C2 and factor B, are probably involved in binding and substrate specificity. C/D X 00 in 00 OH < Q m ra 00 X ^ 00 00 CIH < s (N cd c -o b T h e C o m p l e m e n t S <3 .£fpC| '^ CJ bo o CM o <^ S'S o ^ o .^ .CO -i^ 0 Q ^ ^ o 3 CI ^ r^ O ^ o ° '^ 'T3 CO Q 3 S S « C! CO O CD ;q ^ bo Q o ^ N ? G O o . ^ -i-H 'a ^ s ^ +0 '—IO rd t>0 ^ >s ^ Ci^ O CO CJ ^ i ystem The Complement System FD C1r C1s MASP-1 Hi MASP-2 FB C2 Fl Figure 3. Modular structure of the serine proteases. See Table 1 for key. Additional domain is the scavenger receptor cysteine-rich or CDS domain of FI (\ \). a chain C3 P chain P chain C4 a chain y chain °n^^^^ • •• a chain C5 j_ p chain Key: 400 aa 1 1 A Thioester site Disulphide bonds E3 C3a/C4a/ C5a ll^iiiiiiiii^iill C3d/C4d igure 4. The C3 family.
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