Solution Structure of the Complex between CR2 SCR 1-2 and C3d of Human Complement: An X-ray Scattering and Sedimentation Modelling Study

Background: Sub-retinal pigment epithelial deposits contain complement proteins and bioavailable zinc. Results: Ultracentrifugation and x-ray scattering show that Ͼ100 M zinc induces oligomer formation in each of C3, C3u, and C3b, in analogy to Factor H. Conclusion: Factor H-C3b complexes are precipitated by zinc, which inhibits complement activation. Significance: A potential molecular mechanism for zinc-induced sub-retinal deposit formation is clarified.

Section: Zinc-induced Oligomerization Of C3supporting

confidence: 87%

Zinc-induced self-association of complement C3b and Factor H: Implications for inflammation and age-related macular degeneration

Nan¹,

Tetchner²,

Rodriguez³

et al. 2013

“…Moreover, this structure of the complex showed interactions only between CCP2 of CR2 and C3d and no direct interactions between CCP1 of CR2 and C3d. Two recent studies by the same authors showed that CCP1 of CR2 probably contacts C3d directly (Gilbert et al, 2005;Hannan et al, 2005). Although significant structural differences are apparent between TED of C3 and C3d, the CR2 CCP2-binding site is very similar in the two structures.…”

Section: C3b Fragments Signalingmentioning

confidence: 85%

Structural insights into the central complement component C3

Janssen

Gros

2007

C3 is a central protein of the complement system, which is important to immune defense and provides a link between innate and adaptive immunity. Three pathways of complement activation converge at the activation of C3 yielding a diverse set of biological responses. This versatile and flexible molecule interacts with various proteins to fulfill its functions. Here we review recent insights gained from the crystal structure determinations of human, native C3 and its physiological down-regulation product C3c. The data provided, for the first time, a complete and detailed view of the composition and arrangement of the domains in C3. Comparison of C3 with C3c indicates marked flexibility of the molecule, particularly in the ␣-chain. We discuss the observed domain rearrangements, conformational changes and the location of various protein binding sites. These detailed, and structural, insights are important for developing models of the molecular mechanisms underlying the diverse biological activities of this large and complex molecule.

“…In NMR-based studies of C4BP-1-2, the chemical shift changes accompanying binding to a Streptococcal M protein are consistent with intermodular conformational changes . For CR2-1-2, the highly tilted (closed-vee) modules observed in the crystal structure of the complex with C3d (Gilbert et al, 2005;Szakonyi et al, 2001) are incompatible with the open-vee structure of nonliganded CR2-1-2 inferred from small angle X-ray scattering and sedimentation studies ). However, this story is complex because a crystal structure of the free (noligand) CR2-1-2 exhibits the closed-vee structure (Prota et al, 2002), while solution studies of the complex support the openvee structure (Gilbert et al, 2005).…”

Section: Structure-function Relationships In the Regulators Of Complementioning

confidence: 80%

“…For CR2-1-2, the highly tilted (closed-vee) modules observed in the crystal structure of the complex with C3d (Gilbert et al, 2005;Szakonyi et al, 2001) are incompatible with the open-vee structure of nonliganded CR2-1-2 inferred from small angle X-ray scattering and sedimentation studies ). However, this story is complex because a crystal structure of the free (noligand) CR2-1-2 exhibits the closed-vee structure (Prota et al, 2002), while solution studies of the complex support the openvee structure (Gilbert et al, 2005). Disparities between crystal and solution structures were also observed for another CCPcontaining protein beta-2-glycoprotein I (Bouma et al, 1999;Hammel et al, 2002).…”

Section: Structure-function Relationships In the Regulators Of Complementioning

confidence: 80%

Deciphering complement mechanisms: The contributions of structural biology

Arlaud

Barlow

Gaboriaud

et al. 2007

Since the resolution of the first three-dimensional structure of a complement component in 1980, considerable efforts have been put into the investigation of this system through structural biology techniques, resulting in about a hundred structures deposited in the Protein Data Bank by the beginning of 2007. By revealing its mechanisms at the atomic level, these approaches significantly improve our understanding of complement, opening the way to the rational design of specific inhibitors. This review is co-authored by some of the researchers currently involved in the structural biology of complement and its purpose is to illustrate, through representative examples, how X-ray crystallography and NMR techniques help us decipher the many sophisticated mechanisms that underlie complement functions.