The Crystal Structure of Filamentous Hemagglutinin Secretion Domain and Its Implications for the Two-Partner Secretion Pathway

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 16; pp. 6194 - 6199
• Main Authors: Clantin, Bernard, Hodak, Hélène, Willery, Eve, Locht, Camille, Jacob-Dubuisson, Françoise, Villeret, Vincent, Lipscomb, William N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.04.2004; National Acad Sciences
• Subjects: Adhesins, Bacterial - chemistry; Adhesins, Bacterial - metabolism; Amino Acid Sequence; Architecture; Base Sequence; Biological Sciences; Bordetella pertussis; DNA Primers; Hemagglutinins - chemistry; Hemagglutinins - metabolism; Hydrogen bonds; Models, Molecular; Molecular Sequence Data; Molecules; Passengers; Protein Conformation; Protein transport; Proteins; Recombinant Proteins - chemistry; Scaffolds; Secretion; Sequence Homology, Amino Acid; Virulence Factors, Bordetella - chemistry; Virulence Factors, Bordetella - metabolism; Whooping cough
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0400291101

Filamentous hemagglutinin (FHA), the major 230-kDa adhesin of the whooping cought agent Bordetella pertussis, is one of the most efficiently secreted proteins in Gram-negative bacteria. FHA is secreted by means of the two-partner secretion (TPS) pathway. Several important human, animal, and plant pathogens also secrete adhesins and other virulence factors by using this mode of secretion. A TPS system is composed of two separate proteins, with TpsA the secreted protein and TpsB its associated specific outer-membrane transporter. All TPS-secreted proteins contain a distinctive N-proximal module essential for secretion, the TPS domain. We report here the 1.7-Å structure of a functionally secreted 30-kDa N-terminal fragment of FHA. It reveals that the TPS domain folds into a β-helix, with three extrahelical motifs, a β-hairpin, a four-stranded β-sheet, and an N-terminal capping, mostly formed by the nonconserved regions of the TPS domain. The structure thus explains why the TPS domain is able to initiate folding of the β-helical motifs that form the central domain of the adhesin, because it is itself a β-helical scaffold. It also contains less conserved extrahelical regions most likely involved in specific properties, such as the recognition of the outer-membrane transporter. This structure is representative of the TPS domains found so far in > 100 secreted proteins from pathogenic bacteria. It also provides a mechanistic insight into how protein folding may be linked to secretion in the TPS pathway.