The Partly Folded Back Solution Structure Arrangement of the 30 SCR Domains in Human Complement Receptor Type 1 (CR1) Permits Access to its C3b and C4b Ligands

Furtado, Patricia B.; Huang, Chen Y.; Ihyembe, Demvihin; Hammond, Russell A.; Marsh, Henry C.; Perkins, Stephen J.

doi:10.1016/j.jmb.2007.09.085

Cited by 37 publications

(40 citation statements)

References 52 publications

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“…The deduced values could thus account for the presence of four to six N-linked glycans. The CCP22-30 fragment contains eight predicted N-glycosylation sites (34), but it is likely that all positions are not occupied by carbohydrates, in accordance with previous carbohydrate analyses on full-length CR1 suggesting N-glycosylation of 14 among 25 predicted sites (34). CD spectroscopy was used to assess the correct folding of the fragments.…”

Section: Resultsmentioning

confidence: 58%

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Jacquet

Lacroix²,

Ancelet³

et al. 2013

The Journal of Immunology

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Complement receptor type 1 (CR1) is a membrane receptor expressed on a wide range of cells. It is involved in immune complex clearance, phagocytosis, and complement regulation. Its ectodomain is composed of 30 complement control protein (CCP) modules, organized into four long homologous repeats (A–D). In addition to its main ligands C3b and C4b, CR1 was reported to interact with C1q and mannan-binding lectin (MBL) likely through its C-terminal region (CCP22–30). To decipher the interaction of human CR1 with the recognition proteins of the lectin complement pathway, a recombinant fragment encompassing CCP22–30 was expressed in eukaryotic cells, and its interaction with human MBL and ficolins was investigated using surface plasmon resonance spectroscopy. MBL and L-ficolin were shown to interact with immobilized soluble CR1 and CR1 CCP22–30 with apparent dissociation constants in the nanomolar range, indicative of high affinity. The binding site for CR1 was located at or near the MBL-associated serine protease (MASP) binding site in the collagen stalks of MBL and L-ficolin, as shown by competition experiments with MASP-3. Accordingly, the mutation of an MBL conserved lysine residue essential for MASP binding (K55) abolished binding to soluble CR1 and CCP22–30. The CR1 binding site for MBL/ficolins was mapped to CCP24–25 of long homologous repeat D using deletion mutants. In conclusion, we show that ficolins are new CR1 ligands and propose that MBL/L-ficolin binding involves major ionic interactions between conserved lysine residues of their collagen stalks and surface exposed acidic residues located in CR1 CCP24 and/or CCP25.

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Section: Resultsmentioning

confidence: 58%

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Jacquet

Lacroix²,

Ancelet³

et al. 2013

The Journal of Immunology

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“…The fI will then also cleave iC3b between residues Arg932 and Glu933 generating C3c, which is released into solution, and C3dg, which remains bound to the target. This third cleavage is much slower; under physiological conditions, it is only produced when CR1 serves as a cofactor for cleavage of iC3b by fI (1,7,8).…”

mentioning

confidence: 99%

Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy

Alcorlo

Martı́nez-Barricarte

Fernández

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Activation of C3, deposition of C3b on the target surface, and subsequent amplification by formation of a C3-cleaving enzyme (C3-convertase; C3bBb) triggers the effector functions of complement that result in inflammation and cell lysis. Concurrently, surface-bound C3b is proteolyzed to iC3b by factor I and appropriate cofactors. iC3b then interacts with the complement receptors (CR) of the Ig superfamily, CR2 (CD21), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) on leukocytes, down-modulating inflammation, enhancing B cell-mediated immunity, and targeting pathogens for clearance by phagocytosis. Using EM and small-angle X-ray scattering, we now present a medium-resolution structure of iC3b (24 Å). iC3b displays a unique conformation with structural features distinct from any other C3 fragment. The macroglobulin ring in iC3b is similar to that in C3b, whereas the TED (thioester-containing domain) domain and the remnants of the CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain have moved to locations more similar to where they were in native C3. A consequence of this large conformational change is the disruption of the factor B binding site, which renders iC3b unable to assemble a C3-convertase. This structural model also justifies the decreased interaction between iC3b and complement regulators and the recognition of iC3b by the CR of the Ig superfamily, CR2, CR3, and CR4. These data further illustrate the extraordinary conformational versatility of C3 to accommodate a great diversity of functional activities.

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“…However the resulting curve fit was only good in a Q range out to 0.4 nm 21 . Much improved curve fits out to Q of 1.8-2.0 nm 21 were obtained using the same procedure for complement receptors type 1 (CR1) with 30 SCR domains and type 2 (CR2) with 15 SCR domains (figure 6b,c; Gilbert et al 2006;Furtado et al 2008). The reinvestigation of the FH curve fits showed that very good FH curve fits were obtained (figure 6a), once the occurrence of FH self-association had been identified and its effect minimized (Nan et al 2008;Okemefuna et al in press b).…”

Section: Complement Structures By Constrained Modellingmentioning

confidence: 99%

Constrained solution scattering modelling of human antibodies and complement proteins reveals novel biological insights

Perkins

Okemefuna

Nan

et al. 2009

J. R. Soc. Interface.

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X-ray and neutron-scattering techniques characterize proteins in solution and complement high-resolution structural studies. They are useful when either a large protein cannot be crystallized, in which case scattering yields a solution structure, or a crystal structure has been determined and requires validation in solution. These solution structures are determined by the application of constrained modelling methods based on known subunit structures. First, an appropriate starting model is generated. Next, its conformation is randomized to generate thousands of models for trial-and-error fits. Comparison with the experimental data identifies a small family of best-fit models. Finally, their significance for biological function is assessed. We illustrate this in application to structure determinations for secretory immunoglobulin A, the most prevalent antibody in the human body and a first line of defence in mucosal immunity. We also discuss the applications to the large multi-domain proteins of the complement system, most notably its major regulator factor H, which is important in age-related macular degeneration and renal diseases. We discuss the importance of complementary data from analytical ultracentrifugation, and structural studies of protein -protein complexes. We conclude that constrained scattering modelling makes useful contributions to our understanding of antibody and complement structure and function.

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The Partly Folded Back Solution Structure Arrangement of the 30 SCR Domains in Human Complement Receptor Type 1 (CR1) Permits Access to its C3b and C4b Ligands

Cited by 37 publications

References 52 publications

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Deciphering Complement Receptor Type 1 Interactions with Recognition Proteins of the Lectin Complement Pathway

Unique structure of iC3b resolved at a resolution of 24 Å by 3D-electron microscopy

Constrained solution scattering modelling of human antibodies and complement proteins reveals novel biological insights

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