C2b,3b,4b C3b 2Bb

n C9

Figure 10.11. Classical pathway of complement activation. Top: The C1q,r,s complex can bind to immunoglobulins bound to antigen. At least 1 IgM or 2 IgG are required. Binding of the hexameric C1q protein to Ig results in C1r cleaving and activating C1s. Activated C1s can cleave C4 into C4a (a weak inflammatory peptide) and C4b, which binds to the membrane. This binding is covalent: Cleavage of C4 exposes a reactive thioester bond (between Glu and Cys) in C4b, which reacts with OH-groups in proteins and carbohydrates forming ester and thiol. C4b then recruits C2, which in the C4b-bound state is also cleaved by C1s into C2a (inflammatory peptide with moderate activity) and C2b. The C2b,4b complex recruits C3, which is cleaved to C3a (inflammatory peptide) and C3b. C3b can stay bound as C2b,3b,4b complex, but as each C2b,4b complex cleaves up to 1000 C3 molecules, non-complexed C3b is also formed. Middle: C3b binds factor B, which is then cleaved by factor D, a soluble protease. This results in the formation of a C3b,Bb complex, which also has C3-convertase activity (i.e. splits C3 into C3a and C3b). This leads to a rapid, autocatalytic flooding of the pathogens surface with C5-convertase. Bottom: C2b,3b,4b and C3b2Bb both have C5-convertase activity, they recruit C5 to the membrane, where it is split into C5a (a highly active inflammatory mediator) and C5b. C5b then binds C6, C7 and C8, the latter inserts into the membrane and catalyses the oligomerisation of 10-16 C9 molecules into a large transmembrane pore.

lesser extent C3a) also stimulates the phagocytic response of macrophages by binding to a 7 membrane-spanning domain type of receptor (G-protein coupled). This is particularly important for IgM, as there is no Fc-receptor for this isoform.

CR1 also occurs on erythrocytes. Immune complexes left over after an infection trigger the complement system, covering them with C3b and C4b. This complex binds to the erythrocyte, in liver and spleen the immune complexes are then abstracted from the erythrocytes by specialised macrophages (without destroying the erythrocytes). By this process potentially dangerous immune complexes (which can cause rheumatic diseases, hence the name "rheuma factor") are removed from the blood stream.

10.3.3 How is complement degraded?

Activated component is unstable and degraded rapidly.

There is a complement inhibitor circulating in the blood (C1 inhibitor), which dissociates C1r and C1s from C1q. C1q remains bound to the immunoglobulins on the pathogens, but can no longer activate C4. Inability to form C1Inh leads to hereditary angioneurotic oedema, where uncontrolled complement activation leads to swelling (for example in the trachea).

If C4b does not form a covalent bond with the pathogen's membrane, its thioester is hydrolysed by water and C4b is inactivated.

The C2b,4b complex is dissociated by binding of C4-binding protein (C4BP). The complex between C3 and Bb is dissociated by complement receptor 1, factor H, factor I and decay-accelerating factor (DAF). Factor H is recruited to our cells by binding to sialic acid, which is absent from most pathogens.

CD59 is widely expressed on our cells and prevents the formation of a membrane attack complex, protecting our cells from "stray bullets". Paroxysmal nocturnal haemoglobinuria is caused by the inability to synthesise the glycolipid tail that binds CD59 (and decay-accelerating factor (DAF)) to the cell membrane. This leads to the destruction of erythrocytes by complement, explaining the haemoglobinuria.

10.4 Cellular immunity

Antigen-presenting cells present antigens to T-cells bound to specific cell-surface proteins, called MHC-I 2 and MHC-II (Major Histocompatibility Complex, also known under their German name Hauptlymphozytenantigen, HLA).

2 According to standard nomenclature in human genetics all-caps names like MHC-I are reserved for genes, for the corresponding proteins Mhc-I should be used. How

T-cells have a receptor for the MHC-antigen complex, the T-cell receptor.

10.4.1 The major histocompatibility complex

Sampling proteins produced in our cells: MHC-1

Our cells constantly present samples of the proteins produced by them on their surface, this status is read by T-killer cells. Cancer cells (characterised by expression of embryonal antigens) and virus-infected cells are killed, hopefully before more damage occurs.

Ubiquitin and the proteasome

Proteins no longer needed in our cells are marked by linking several copies of ubiquitin to it, a 8.6 kDa protein. Transfer of ubiquitin is performed by a group of ubiquitin-ligases, of which 3 classes exist. E1-ligase (UbA1) (see fig. 10.12) forms a thioester-bond with the C-terminal glycine-residue of ubiquitin in an ATP-dependent reaction. This activated ubiquitin is then transferred to an E2-ligase (UbCs) and from there to an E3-ligase. All three ligases bind ubiquitin as thioester. There is only one E1 (UbA1) but several UbCs and many E3-ligases, which transfer the ubiquitin to the e-amino-group of a lysine in the proteins to be destroyed, forming an isopeptide bond. Ubiquitin contains several Lys-residues, whose e-amino groups form iso-peptide bonds with the C-terminal Gly of other ubiquitin molecules, resulting in long chains of poly-ubiquitin. For the discovery of ubiquitin A. ClEOHANOVER, A. Hershko & I. Rose received the Nobel-Price for Chemistry in 2004.

Ubiquitin is the most well known member of a whole family of proteins with ubiquitin-fold, which are transferred to proteins by a similar mechanism as ubiquitin, except that transfer is often by an E2-ligase directly. E3-ligases are required for ubiquitin presumably because of the large number of different proteins labelled with this marker. These ubiquitin-like modifiers (UbLs) are involved in the regulation of endocytosis, apoptosis, cell cycle, DNA repair and other processes. There are even ubiquitin like proteins (Isg15 and Fat10), which are regulated by interferon and modulate immune response. The mechanisms involved in these regulatory pathways is however poorly understood. Poly-ubiquitins formed via Lys-48 are recognised by the proteasome, special isopeptidases are able to remove ubiquitin from iso-peptide bonds and recycle it. Formation of poly-ubiquitin via Lys-63 seems to be involved in regulatory processes like receptor-mediated endocytosis.

ever, in the literature the all caps spelling is found for many proteins, including MHC. I will follow the common use here and use italics (MHC-1) to indicate genes. May be one day we will get a universally accepted, perhaps even species independent, nomenclature.

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