Identification of a Family of Streptococcal Surface Proteins with Extremely Repetitive Structure

Wästfelt, Maria; Stålhammar‐Carlemalm, Margaretha; Delisse, Anne-Marie; Cabezón, Teresa; Lindahl, Gunnar

doi:10.1074/jbc.271.31.18892

Cited by 120 publications

(166 citation statements)

References 22 publications

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“…The N-terminal regions of Alps share 60 -100% similarity at the amino acid level (Fig. 3), suggesting that they may function similarly (17,23,37,39).…”

Section: Discussionmentioning

confidence: 99%

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Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

Auperin

Bolduc

Baron

et al. 2005

Journal of Biological Chemistry

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Group B Streptococcus (GBS) is the leading cause of bacterial pneumonia, sepsis, and meningitis among neonates and an important cause of morbidity among pregnant women and immunocompromised adults. Invasive diseases due to GBS are attributed to the ability of the pathogen to translocate across human epithelial surfaces. The alpha C protein (ACP) has been identified as an invasin that plays a role in internalization and translocation of GBS across epithelial cells. The soluble N-terminal domain of ACP (NtACP) blocks the internalization of GBS. We determined the 1.86-Å resolution crystal structure of NtACP comprising residues Ser 52 through Leu 225 of the full-length ACP. NtACP has two domains, an N-terminal ␤-sandwich and a C-terminal three-helix bundle. Structural and topological alignments reveal that the ␤-sandwich shares structural elements with the type III fibronectin fold (FnIII), but includes structural elaborations that make it unique. We have identified a potential integrin-binding motif consisting of Lys-Thr-Asp 146 , Arg 110 , and Asp 118 . A similar arrangement of charged residues has been described in other invasins. ACP shows a heparin binding activity that requires NtACP. We propose a possible heparin-binding site, including one surface of the three-helix bundle, and nearby portions of the sandwich and repeat domains. We have validated this prediction using assays of the heparin binding and cell-adhesion properties of engineered fragments of ACP. This is the first crystal structure of a member of the highly conserved Gram-positive surface alpha-like protein family, and it will enable the internalization mechanism of GBS to be dissected at the atomic level.Group B Streptococcus (GBS) 1 (Streptococcus agalactiae) remains the leading cause of invasive bacterial diseases in neonates, despite its decline in prevalence during the last decade because of intrapartum chemoprophylatic therapy (1, 2). It is also an important cause of morbidity in pregnant women and non-pregnant adults with underlying medical conditions (3-5). GBS colonizes the human gastrointestinal and genitourinary tracts and may cause chorioamnionitis and urinary tract infection in pregnant women and a range of invasive infections in elderly and immunocompromised adults (1, 6 -8). During labor and delivery, GBS may be transmitted to neonates, causing pneumonia, sepsis, or meningitis. Four to six percent of all neonatal GBS infections result in death (6, 9). In vitro, GBS adheres to (10, 11), internalizes within (12-14), and translocates across (15) intact human epithelial and endothelial cells. Little is known about the bacterial components that allow this pathogen to adhere to and penetrate cellular membranes. Previous studies suggest that surface proteins are significantly involved in the process (11, 16). The surface-expressed GBS alpha C protein (ACP) has been shown to act as an invasin (15). ACP is the prototype of a family of surface-expressed proteins containing long tandem repeats (alpha-like proteins (Alp)). Members of this famil...

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“…The N-terminal regions of Alps share 60 -100% similarity at the amino acid level (Fig. 3), suggesting that they may function similarly (17,23,37,39).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the first methionine of the recombinant proteins is numbered Met 39 , as the first residue of the alpha C protein 2 N-terminal domain in the GenBank TM data base is Ser 52 .…”

Section: Methodsmentioning

confidence: 99%

Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

Auperin

Bolduc

Baron

et al. 2005

Journal of Biological Chemistry

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“…The existence of a protein family was suggested by the observation that the Rib protein, purified from a type III GBS strain, is a homolog of the alpha C protein gene. It has a similar N-terminal encoding region, a series of 12 237-bp identical tandem repeats, and a highly conserved C-terminal encoding region (10). Phenotypic characteristics of alpha-like proteins from type V and VIII GBS suggest that these proteins also are related (4,5,11) and likely possess a similar genetic organization.…”

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confidence: 99%

Mosaicism in the alpha-like protein genes of group B streptococci

Lachenauer

Creti

Michel

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

110

165

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Members of a family of repeat-containing surface proteins of group B streptococci (GBS) defined by the alpha C and Rib proteins exhibit size variability and cross-reactivity and have been studied as potential vaccine components. We report evidence of horizontal DNA transfer with subsequent recombination as a mechanism generating diversity within this antigen family. Alp2 and Alp3 are additional members of the alpha C protein family identified in strains of the emerging GBS serotypes V and VIII. Each contains an overall genetic organization highly similar to that of the alpha C and Rib proteins, including a tandem repeat region and conserved N-and C-terminal regions. Among different strains, protein size varies according to the number of tandem repeats within the corresponding gene. Unlike the alpha C and Rib proteins, however, the newly described alpha-like proteins contain other regions, including one similar to the IgA-binding region of the GBS beta C protein, a nontandem repeat region, and an isolated repeat highly homologous to the alpha C repeat. Sequence analysis of the regions flanking the alpha C protein gene on a 13.7-kb insert reveals several ORFs that are likely to be involved in basic metabolic pathways. Analysis of corresponding flanking regions in other GBS strains, including the parent strains of the newly described alpha-like proteins, shows striking conservation among all strains studied. These findings indicate that the alpha-like proteins are encoded by mosaic variants at a single genomic locus and suggest that recombination after horizontal DNA transfer is a means of generating diversity within this protein family.

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“…Molecular characterization of the R28 protein [24] showed that it is a member of a family of extremely repetitive surface proteins first identified in the group B streptococcus (GBS; Streptococcus agalactiae) [26], which is often found in the normal vaginal flora and causes serious invasive disease in newborns [27]. The protein family that includes R28 was first defined by the GBS proteins Rib and α [26,28,29] and among these GBS proteins R28 is most closely related to Rib (Fig.…”

Section: Puerperal Fever and The R28 Proteinmentioning

confidence: 99%

“…The protein family that includes R28 was first defined by the GBS proteins Rib and α [26,28,29] and among these GBS proteins R28 is most closely related to Rib (Fig. 2).…”

Section: Puerperal Fever and The R28 Proteinmentioning

confidence: 99%

Host–pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development

Areschoug

Carlsson

Stålhammar‐Carlemalm

et al. 2004

Vaccine

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Host-pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development. Link to publication Citation for published version (APA): Areschoug, T., Carlsson, F., Stålhammar-Carlemalm, M., & Lindahl, G. (2004). Host-pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development. Vaccine, 22 Suppl 1(Suppl 1), S9-S14. DOI: 10.1016DOI: 10. /j.vaccine.2004 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal

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Identification of a Family of Streptococcal Surface Proteins with Extremely Repetitive Structure

Cited by 120 publications

References 22 publications

Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

Crystal Structure of the N-terminal Domain of the Group B Streptococcus Alpha C Protein

Mosaicism in the alpha-like protein genes of group B streptococci

Host–pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development

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