Trimeric structure and conformational equilibrium of M-ficolin fibrinogen-like domain

Michikazu Tanio,Toshiyuki Kohno,Shin Kondo,Shigetoshi Sugio

doi:10.1107/s0909049507054325

Michikazu Tanio, Toshiyuki Kohno + Show 2 more

Open Access

https://doi.org/10.1107/s0909049507054325

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Abstract

Ficolins are pathogen-recognition molecules in innate immune systems. The crystal structure of the human M-ficolin recognition domain (FD1) has been determined at 1.9 A resolution, and compared with that of the human fibrinogen gamma fragment, tachylectin-5A, L-ficolin and H-ficolin. The overall structure of FD1 is similar to that of the other proteins, although the peptide bond between Asp282 and Cys283, which is in a predicted ligand-binding site, is a normal trans bond, unlike the cases of the other proteins. Analysis of the pH-dependent ligand-binding activity of FD1 in solution suggested that a conformational equilibrium between active and non-active forms in the ligand-binding region, involving cis-trans isomerization of the Asp282-Cys283 peptide bond, contributes to the discrimination between self and non-self, and that the pK(a) values of His284 are 6.1 and 6.3 in the active and non-active forms, respectively.

Highlights

Innate immune systems play a crucial role as the first line of defense against pathogens, and are present in all multicellular organisms, including humans (Fujita et al, 2004)
Ficolins, which are composed of a collagen-like domain at the N-terminus and a fibrinogen-like domain (FBG) at the C-terminus, are one of the most important groups of pattern-recognition molecules in innate immune systems
The amino acid sequence homologies between M-ficolin and L-ficolin, and between H-ficolin and either L-ficolin or M-ficolin, are 80 and 48%, respectively (Endo et al, 1996; Sugimoto et al, 1998). These ficolins are associated with the mannose binding lectin-associated serine proteases, and the complexes activate the lectin-complement pathway (Fujita et al, 2004; Liu et al, 2005; Frederiksen et al, 2005)

Summary

Introduction

Innate immune systems play a crucial role as the first line of defense against pathogens, and are present in all multicellular organisms, including humans (Fujita et al, 2004). The amino acid sequence homologies between M-ficolin and L-ficolin, and between H-ficolin and either L-ficolin or M-ficolin, are 80 and 48%, respectively (Endo et al, 1996; Sugimoto et al, 1998) These ficolins are associated with the mannose binding lectin-associated serine proteases, and the complexes activate the lectin-complement pathway (Fujita et al, 2004; Liu et al, 2005; Frederiksen et al, 2005). To investigate the detailed mechanism of discrimination between self and non-self by ficolins, we have determined the crystal structure of the human M-ficolin FBG domain (FD1) at 1.9 Aresolution, using synchrotron radiation at beamline BL24XU at the SPring-8 facility in Japan (PDB code 2d39; Tanio et al, 2006, 2007). The crystal structure of FD1, together with its pHdependent ligand binding activity, provides insight into the discrimination mechanism by ficolins

Trimeric structure of FD1

Conformational equilibrium of the ligand-binding site of FD1