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Nick Stub Laursen

Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System

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Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System. / Pedersen, Dennis V; Gadeberg, Trine A F; Thomas, Caroline; Joram, Nicolas; Jensen, Rasmus K; Mazarakis, Sofia M M; Revel, Margot; El Sissy, Carine; Petersen, Steen V; Lindorff-Larsen, Kresten; Thiel, Steffen; Laursen, Nick S; Fremeaux-Bacchi, Véronique; Andersen, Gregers R.

In: Frontiers in Immunology, Vol. 10, 2007, 08.2019.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Pedersen, DV, Gadeberg, TAF, Thomas, C, Joram, N, Jensen, RK, Mazarakis, SMM, Revel, M, El Sissy, C, Petersen, SV, Lindorff-Larsen, K, Thiel, S, Laursen, NS, Fremeaux-Bacchi, V & Andersen, GR 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

APA

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, 10, [2007]. https://doi.org/10.3389/fimmu.2019.02007

CBE

Pedersen DV, Gadeberg TAF, Thomas C, Joram N, Jensen RK, Mazarakis SMM, Revel M, El Sissy C, Petersen SV, Lindorff-Larsen K, Thiel S, Laursen NS, Fremeaux-Bacchi V, Andersen GR. 2019. Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System. Frontiers in Immunology. 10:Article 2007. https://doi.org/10.3389/fimmu.2019.02007

MLA

Vancouver

Author

Pedersen, Dennis V ; Gadeberg, Trine A F ; Thomas, Caroline ; Joram, Nicolas ; Jensen, Rasmus K ; Mazarakis, Sofia M M ; Revel, Margot ; El Sissy, Carine ; Petersen, Steen V ; Lindorff-Larsen, Kresten ; Thiel, Steffen ; Laursen, Nick S ; Fremeaux-Bacchi, Véronique ; Andersen, Gregers R. / Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System. In: Frontiers in Immunology. 2019 ; Vol. 10.

Bibtex

@article{d98609c2061f4ec5b1099860c5a6a47d,
title = "Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System",
abstract = "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 Fl 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.",
keywords = "Complement, Complement component C3, Convertase, Crystal structure, Factor B, Properdin, Regulation, ACTIVATION, MOLECULAR-DYNAMICS, complement component C3, convertase, PATHWAY C3 CONVERTASE, factor B, DEFICIENCY, REGULATOR, properdin, regulation, FAMILIES, crystal structure, ALTERNATIVE-PATHWAY, COMPONENT, INHIBITOR, complement, THROMBOSPONDIN",
author = "Pedersen, {Dennis V} and Gadeberg, {Trine A F} and Caroline Thomas and Nicolas Joram and Jensen, {Rasmus K} and Mazarakis, {Sofia M M} and Margot Revel and {El Sissy}, Carine and Petersen, {Steen V} and Kresten Lindorff-Larsen and Steffen Thiel and Laursen, {Nick S} and V{\'e}ronique Fremeaux-Bacchi and Andersen, {Gregers R}",
year = "2019",
month = aug,
doi = "10.3389/fimmu.2019.02007",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Research Foundation",

}

RIS

TY - JOUR

T1 - Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System

AU - Pedersen, Dennis V

AU - Gadeberg, Trine A F

AU - Thomas, Caroline

AU - Joram, Nicolas

AU - Jensen, Rasmus K

AU - Mazarakis, Sofia M M

AU - Revel, Margot

AU - El Sissy, Carine

AU - Petersen, Steen V

AU - Lindorff-Larsen, Kresten

AU - Thiel, Steffen

AU - Laursen, Nick S

AU - Fremeaux-Bacchi, Véronique

AU - Andersen, Gregers R

PY - 2019/8

Y1 - 2019/8

N2 - 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 Fl 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.

AB - 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 Fl 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.

KW - Complement

KW - Complement component C3

KW - Convertase

KW - Crystal structure

KW - Factor B

KW - Properdin

KW - Regulation

KW - ACTIVATION

KW - MOLECULAR-DYNAMICS

KW - complement component C3

KW - convertase

KW - PATHWAY C3 CONVERTASE

KW - factor B

KW - DEFICIENCY

KW - REGULATOR

KW - properdin

KW - regulation

KW - FAMILIES

KW - crystal structure

KW - ALTERNATIVE-PATHWAY

KW - COMPONENT

KW - INHIBITOR

KW - complement

KW - THROMBOSPONDIN

UR - http://www.scopus.com/inward/record.url?scp=85072013159&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2019.02007

DO - 10.3389/fimmu.2019.02007

M3 - Journal article

C2 - 31507604

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 2007

ER -