Mannan-Binding Lectin: Structure, Oligomerization, and Flexibility Studied by Atomic Force Microscopy

Jensenius, Henriette; Klein, Dionne; Hecke, Martin van; Oosterkamp, Tjerk H.; Schmidt, Thomas; Jensenius, Jens C.

doi:10.1016/j.jmb.2009.05.083

Cited by 53 publications

(63 citation statements)

References 59 publications

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“…MBL is also heterogeneous by stoichiometry, with the smallest form being dimer of polypeptide trimers formed through the collagen stem, but such dimeric MBL-MASP complexes do not bind carbohydrate patterns with a high enough avidity to allow for efficient activation of complement. MBL trimers and tetramers are the dominating form occurring naturally in humans, but higher oligomers are also present, and their intersubunit orientation is quite variable (25). In MASP-2, flexibility is presumably present within the CUB2 domain (26), at the CUB2-CCP1 linkage (27), and at the CCP2-SP linkage, as shown here.…”

Section: Discussionsupporting

confidence: 52%

Structural basis for activation of the complement system by component C4 cleavage

Kidmose¹,

Laursen²,

Dobó

et al. 2012

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

110

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An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4·MASP-2 substrate·enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C-CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme-substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen-antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.crystallography | pattern recognition | proteolysis | structural biology

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Section: Discussionsupporting

confidence: 52%

Structural basis for activation of the complement system by component C4 cleavage

Kidmose¹,

Laursen²,

Dobó

et al. 2012

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

110

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“…The oligomers formed by the C72 mutants had apparent sizes below that of aldolase (158 kDa), whereas the wild-type lectin formed much larger oligomers with at least 35 subunits predicted. The native size range of rSSL oligomers is consistent with the 67-subunit MBL oligomers detected by atomic force microscopy [37], whereas the smaller sized oligomers formed by the C72 mutants are more in line with those found in other fish type VII lectins. The oligomers of the C72 mutants were consistent in size with most other fish group VII lectins, which lack cysteine at that position.…”

Section: Discussionsupporting

confidence: 84%

Cystine-mediated oligomerization of the Atlantic salmon serum C-type lectin

Hudson

Mattatall

Uribe

et al. 2011

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…In conclusion, much to our surprise, and despite significant structural and functional differences between the C1 complex and MBL/ficolin-MASP complexes (53), it appears that, in functional terms, MASP-1 and MASP-2 act in an analogous manner to C1r and C1s. In simple terms, MASP-1 being 20-fold more abundant than MASP-2 (19), and having a much higher propensity for autoactivation, seems to dramatically increase the rate of activation of MASP-2.…”

Section: Discussionmentioning

confidence: 72%

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

Degn

Jensen

Hansen

et al. 2012

The Journal of Immunology

Self Cite

142

152

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The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.

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Mannan-Binding Lectin: Structure, Oligomerization, and Flexibility Studied by Atomic Force Microscopy

Cited by 53 publications

References 59 publications

Structural basis for activation of the complement system by component C4 cleavage

Structural basis for activation of the complement system by component C4 cleavage

Cystine-mediated oligomerization of the Atlantic salmon serum C-type lectin

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

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