Structural Insights into the Initiating Complex of the Lectin Pathway of Complement Activation

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The proteolytic cascade of the complement system is initiated when pattern-recognition molecules (PRMs) bind to ligands, resulting in the activation of associated proteases. In the lectin pathway of complement, the complex of mannan-binding lectin (MBL) and MBL-associated serine protease-1 (MASP-1) initiates the pathway by activating a second protease, MASP-2. Here we present a structural study of a PRM/MASP complex and derive the overall architecture of the 450 kDa MBL/MASP-1 complex using small-angle X-ray scattering and electron microscopy. The serine protease (SP) domains from the zymogen MASP-1 dimer protrude from the cone-like MBL tetramer and are separated by at least 20 nm. This suggests that intracomplex activation within a single MASP-1 dimer is unlikely and instead supports intercomplex activation, whereby the MASP SP domains are accessible to nearby PRM-bound MASPs. This activation mechanism differs fundamentally from the intracomplex initiation models previously proposed for both the lectin and the classical pathway.

OriginalsprogEngelsk
TidsskriftStructure
Vol/bind23
Nummer2
Sider (fra-til)342-351
Antal sider10
ISSN0969-2126
DOI
StatusUdgivet - 3 feb. 2015

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