Staphylococcus aureus SdrE captures complement factor H's C-terminus via a novel ‘close, dock, lock and latch' mechanism for complement evasion

Abstract

Complement factor H (CFH) is a soluble complement regulatory protein essential for the down-regulation of the alternative pathway on interaction with specific markers on the host cell surface. It recognizes the complement component 3b (C3b) and 3d (C3d) fragments in addition to self cell markers (i.e. glycosaminoglycans, sialic acid) to distinguish host cells that deserve protection from pathogens that should be eliminated. The Staphylococcus aureus surface protein serine–aspartate repeat protein E (SdrE) was previously reported to bind human CFH as an immune-evasion tactic. However, the molecular mechanism underlying SdrE–CFH-mediated immune evasion remains unknown. In the present study, we identified a novel region at CFH's C-terminus (CFH1206–1226), which binds SdrE N2 and N3 domains (SdrEN2N3) with high affinity, and determined the crystal structures of apo-SdrEN2N3 and the SdrEN2N3–CFH1206–1226 complex. Comparison of the structure of the CFH–SdrE complex with other CFH structures reveals that CFH's C-terminal tail flips from the main body to insert into the ligand-binding groove of SdrE. In addition, SdrEN2N3 adopts a ‘close’ state in the absence of CFH, which undergoes a large conformational change on CFH binding, suggesting a novel ‘close, dock, lock and latch' (CDLL) mechanism for SdrE to recognize its ligand. Our findings imply that SdrE functions as a ‘clamp' to capture CFH's C-terminal tail via a unique CDLL mechanism and sequesters CFH on the surface of S. aureus for complement evasion.

Enolase From Aspergillus fumigatus Is a Moonlighting Protein That Binds the Human Plasma Complement Proteins Factor H, FHL-1, C4BP, and Plasminogen

“…For C. albicans four factor H binding proteins are so far identified i.e., pH-regulated antigen 1 (Pra1), glycerol-3-phosphate dehydrogenase 2 (Gpd2), high-affinity glucose transporter 1 (Hgt1), and phosphoglycerate mutase (Gpm1) (35). The Gram positive bacterium S. aureus has two identified factor H ligands, serine–aspartate repeat protein E (SdrE) and Staphylococcus aureus binder of IgG (Sbi) (59, 60). For Streptococcus pneumoniae two factor H ligands, i.e., Tuf from also recruits plasma regulators and PspC are identified (16).…”

Structural insights into the intermolecular interaction of the adhesin SdrC in the pathogenicity of Staphylococcus aureus

“…In contrast to the apo form of SdrE, in which the intrinsic loop A-B closed the ligand-binding cleft between N2 and N3 (Zhang et al, 2017), the putative binding pocket was exposed with no shelter in our SdrC dimer, similar to as in SdrG. With the C-terminus clamped, SdrC-N2N3 could not finish the subsequent process of 'lock and latch' upon ligand binding ( Fig.…”

“…of SdrE or SdrG, the ligand was latched tightly within the binding groove between the N2 and N3 subdomains, making the C-terminus stretch to form an antiparallel -sheet with N2 (Zhang et al, 2017;Ponnuraj et al, 2003). However, in the case of our SdrC structure a local shift starting from the end of 12 in N3 changed the track of the C-terminus and triggered a 60-70 deviation (Fig.…”

Hijacking Factor H for Complement Immune Evasion

“…(E) FH binding to deposited C3b on the pathogen surface results in a transformational change in S. aureus FH binding protein, SdrE, from a closed to open state. In the open state, SdrE facilitates the docking of CCP 20 into a ligand binding groove ( 136 ). (F) S. pneumoniae FH binding protein, PspC, via its tyrosine 90 residue acts like a key inserting into a hydrophobic lock formed by four hydrophobic residues of FH CCP 9 ( 146 ).…”

“…In the model proposed by Zhang and colleagues, S. aureus surface protein serine–aspartate repeat protein E (SdrE) tightly binds a 21 amino acid region of CCP 20 not involved in the binding of C3d or of host cell markers (i.e., heparin, GAGs, and sialic acid) ( 85 , 136 ). Upon FH binding to deposited C3b on the pathogen surface, SdrE undergoes a transformational change from a close to open state, which facilitates the docking of CCP 20 into a ligand binding groove ( 136 ). SdrE functions as a “clamp” to stabilize the SdrE-FH complex by locking and latching the FH tail into its ligand binding groove ( 136 ).…”