Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond

Summary Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation of the amplification pathway of the complement cascade. Although properdin (FP) is required in vivo to sustain a functional...

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Bibliographic Details
Published in:Immunological reviews 2023-01, Vol.313 (1), p.46-59
Main Authors: Pedersen, Dennis Vestergaard, Lorentzen, Josefine, Andersen, Gregers Rom
Format: Article
Language:English
Subjects:
Alternative pathway
complement
Complement Activation
Complement component C3b
Complement Pathway, Alternative
convertase
Humans
immune evasion
Immune system
In vivo methods and tests
innate immune system
Invited Review
Invited Reviews
Molecular interactions
Molecular modelling
Mutation
Oligomerization
Properdin
Properdin - genetics
Properdin - metabolism
Proteins
Structure-function relationships
Ticks
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Summary:Summary Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation of the amplification pathway of the complement cascade. Although properdin (FP) is required in vivo to sustain a functional alternative pathway, structural studies have been lagging behind due to the extended structure and polydisperse nature of FP. We review recent progress with respect to structure determination of FP and its proconvertase/convertase complexes. These structures identify in detail regions in C3b, factor B and FP involved in their mutual interactions. Structures of FP oligomers obtained by integrative studies have shed light on how FP activity depends on its oligomerization state. The accumulated structural knowledge allows us to rationalize the effect of point mutations causing FP deficiency. The structural basis for FP inhibition by the tick CirpA proteins is reviewed and the potential of alphafold2 predictions for understanding the interaction of FP with other tick proteins and the NKp46 receptor on host immune cells is discussed. The accumulated structural knowledge forms a comprehensive basis for understanding molecular interactions involving FP, pathological conditions arising from low levels of FP, and the molecular strategies used by ticks to suppress the alternative pathway.
ISSN:0105-2896
1600-065X
DOI:10.1111/imr.13129