Complement Factor D (Adipsin)

The complement activation, amplification, and progression are strictly regulated by a series of factors and proteins. Complement factor D (CFD) is an indispensable regulator of the alternative pathway of complement activation.

CFD, also known as adipsin, is a serine protease synthesized by the liver and adipocytes. Human CFD is a non-glycosylated single polypeptide chain with two variants, a 253-amino acid variant 1 and a 260-amino acid variant 2. The structure of CFD is characterized by two antiparallel β-barrel domains, which are quite similar to other serine proteases. CFD differs from other serine proteases in that there are several unique amino acid substitutions, leading to significant changes in the catalytic domain and substrate-specific loops. Human CFD circulates in the plasma in a deactivated state until it binds to substrate and undergoes conformation change.

In the activation of the complement alternative pathway, CFD cleaves its unique substrate, C3b (or C3(H₂O)) bound complement factor B (CFB), between Arg233 and Lys234. The cleavage generates the alternative pathway C3 convertases C3bBb (or C3(H₂O)Bb). Thus, CFD, serving as a key and rate-limiting component in the alternative pathway cascade. Additionally, it has been indicated that CFD also plays an unexpected role in triglyceride synthesis in adipose tissue and energy balance regulation. Human CFD deficiency can cause an increased risk of infections, especially in Neisseria infections. CFD inhibitor has been developed for the treatment of disorders caused by complement over-activation, such as paroxysmal nocturnal hemoglobinuria (PNH).

Fig. 1 The functions of complement factor D in the alternative complement pathway.¹

Reference

1. From Wikipedia: commons: By user:Kimbar, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Formowanie_MAC.svg