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Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System
- Source :
- Frontiers in Immunology, Frontiers in Immunology, Frontiers, 2019, 10, pp.2007. ⟨10.3389/fimmu.2019.02007⟩, Frontiers in immunology 10, 2007 (2019). doi:10.3389/fimmu.2019.02007, Pedersen, D V, Gadeberg, T A F, Thomas, C, Wang, Y, Joram, N, Jensen, R K, Mazarakis, S M M, Revel, M, El Sissy, C, Petersen, S V, Lindorff-Larsen, K, Thiel, S, Laursen, N S, Fremeaux-Bacchi, V & Andersen, G R 2019, ' Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System ', Frontiers in Immunology, vol. 10, 2007 . https://doi.org/10.3389/fimmu.2019.02007, Frontiers in Immunology, Vol 10 (2019), Pedersen, D V, Gadeberg, T A F, Thomas, C, Joram, N, Jensen, R K, Mazarakis, S M M, Revel, M, El Sissy, C, Petersen, S V, Lindorff-Larsen, K, Thiel, S, Laursen, N S, Fremeaux-Bacchi, V & Andersen, G R 2019, ' Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System ', Frontiers in Immunology, vol. 10, 2007 . https://doi.org/10.3389/fimmu.2019.02007
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- International audience; Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.
- Subjects :
- Models, Molecular
0301 basic medicine
Protein Conformation
THROMBOSPONDIN
Complement C3-C5 Convertases
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
FAMILIES
ACTIVATION
0302 clinical medicine
Immunology and Allergy
complement
Original Research
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
Chemistry
INHIBITOR
regulation
3. Good health
DEFICIENCY
properdin
REGULATOR
Protein Binding
lcsh:Immunologic diseases. Allergy
crystal structure
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
PATHWAY C3 CONVERTASE
Immunology
Complement factor B
complement component C3
Structure-Activity Relationship
03 medical and health sciences
ALTERNATIVE-PATHWAY
factor B
Humans
ddc:610
Binding site
[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity
Thrombospondin
Binding Sites
Properdin
Complement System Proteins
convertase
COMPONENT
C3-convertase
Complement system
HEK293 Cells
030104 developmental biology
MOLECULAR-DYNAMICS
Mutation
Proteolysis
Alternative complement pathway
Biophysics
Protein Multimerization
lcsh:RC581-607
Protein Processing, Post-Translational
Function (biology)
030215 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology, Frontiers in Immunology, Frontiers, 2019, 10, pp.2007. ⟨10.3389/fimmu.2019.02007⟩, Frontiers in immunology 10, 2007 (2019). doi:10.3389/fimmu.2019.02007, Pedersen, D V, Gadeberg, T A F, Thomas, C, Wang, Y, Joram, N, Jensen, R K, Mazarakis, S M M, Revel, M, El Sissy, C, Petersen, S V, Lindorff-Larsen, K, Thiel, S, Laursen, N S, Fremeaux-Bacchi, V & Andersen, G R 2019, ' Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System ', Frontiers in Immunology, vol. 10, 2007 . https://doi.org/10.3389/fimmu.2019.02007, Frontiers in Immunology, Vol 10 (2019), Pedersen, D V, Gadeberg, T A F, Thomas, C, Joram, N, Jensen, R K, Mazarakis, S M M, Revel, M, El Sissy, C, Petersen, S V, Lindorff-Larsen, K, Thiel, S, Laursen, N S, Fremeaux-Bacchi, V & Andersen, G R 2019, ' Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System ', Frontiers in Immunology, vol. 10, 2007 . https://doi.org/10.3389/fimmu.2019.02007
- Accession number :
- edsair.doi.dedup.....97d4c896d5126beb3d871f0a79cf2e22