11 research outputs found
Monospecific inhibitors show that both mannan-binding lectin-associated serine protease (MASP)-1 and -2 are essential for lectin pathway activation and reveal structural plasticity of MASP-2.
The lectin pathway is an antibody-independent activation route
of the complement system. It provides immediate defense against
pathogens and altered self-cells, but it also causes severe
tissue damage after stroke, heart attack and other ischemia
reperfusion injuries. The pathway is triggered by target-binding
of pattern recognition molecules leading to the activation of
zymogen mannan-binding lectin-associated serine proteases
(MASPs). MASP-2 is considered as the autonomous pathway-
activator while MASP-1 as an auxiliary component. We evolved a
pair of monospecific MASP inhibitors. In accordance with the key
role of MASP-2, the MASP-2 inhibitor completely blocks the
lectin pathway activation. Importantly, the MASP-1 inhibitor
does the same demonstrating that MASP-1 is not an auxiliary but
an essential pathway component. We report the first Michaelis-
like complex structures of MASP-1 and MASP-2 formed with
substrate-like inhibitors. The 1.28 A resolution MASP-2
structure reveals significant plasticity of the protease
suggesting that either an induced fit or a conformational
selection mechanism should contribute to the extreme specificity
of the enzyme