PDBsum entry 2hr0

Immune system

PDB id: 2hr0

Contents

Protein chains

641 a.a.

907 a.a.

Ligands

THC

Waters ×708

References listed in PDB file

Key reference

Title

The structure of complement c3b provides insights into complement activation and regulation.

Authors

A.Abdul ajees, K.Gunasekaran, J.E.Volanakis, S.V.Narayana, G.J.Kotwal, H.M.Murthy.

Ref.

Nature, 2006, 444, 221-225. [DOI no: 10.1038/nature05258]

PubMed id

17051152

Abstract

The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases. Complement component 3 (C3) occupies a central position because of the manifold biological activities of its activation fragments, including the major fragment, C3b, which anchors the assembly of convertases effecting C3 and C5 activation. C3 is converted to C3b by proteolysis of its anaphylatoxin domain, by either of two C3 convertases. This activates a stable thioester bond, leading to the covalent attachment of C3b to cell-surface or protein-surface hydroxyl groups through transesterification. The cleavage and activation of C3 exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), complement receptor 1 (CR1, CD35) and viral molecules such as vaccinia virus complement-control protein. C3b associates with these molecules in different configurations and forms complexes mediating the activation, amplification and regulation of the complement response. Structures of C3 and C3c, a fragment derived from the proteolysis of C3b, have revealed a domain configuration, including six macroglobulin domains (MG1-MG6; nomenclature follows ref. 5) arranged in a ring, termed the beta-ring. However, because neither C3 nor C3c is active in complement activation and regulation, questions about function can be answered only through direct observations on C3b. Here we present a structure of C3b that reveals a marked loss of secondary structure in the CUB (for 'complement C1r/C1s, Uegf, Bmp1') domain, which together with the resulting translocation of the thioester domain provides a molecular basis for conformational changes accompanying the conversion of C3 to C3b. The total conformational changes make many proposed ligand-binding sites more accessible and create a cavity that shields target peptide bonds from access by factor I. A covalently bound N-acetyl-l-threonine residue demonstrates the geometry of C3b attachment to surface hydroxyl groups.

Figure 1.
Figure 1: C3, C3b and C3c. a, Top: diagrams showing domain movement on conversion to C3b. Red, C345C; yellow, MG7; grey, MG8; blue, ANA; purple, MG3; violet, CUBg and CUBf; green, TED. Bottom: schematic representation of the diagrams in the top row. The AcT-binding site is indicated by a white arrowhead. LNK, linker domain (residues 578–645). b, Largest changes. Left: positions of CUBg and CUBf in C3b (pink and blue), C3 (brown and cyan) and TED (red, C3; green, C3b); displacement of TED is visible. Right: top, changes in C345C (blue) and ANC (magenta); bottom, MG8 movement, from C3 (magenta) to C3b (blue).

Figure 4.
Figure 4: C3b inactivation. a, Electrostatic surface charge on C3b (left) and C3, contoured at 5 e Å^-2. The C3b surface is significantly more negative. b, Two Arg-Ser bonds and an Arg-Glu peptide bond that are cleaved in converting C3b to C3c are shown as sticks. Solvent-accessible surfaces of the -ring domains, coloured white, yellow, orange and beige, and TED (green) and CUBg and CUBf (magenta) are also shown. Sequestration of scissile bonds in a cavity that shields them from access to large proteases such as factor I is evident.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2006, 444, 221-225) copyright 2006.