The three-dimensional structure of the tenth type III module of fibronectin: An insight into RGD-mediated interactions

Main, Alison L.; Harvey, Timothy S.; Baron, Martín; Boyd, Jonathan; Campbell, Iain D.

doi:10.1016/0092-8674(92)90600-h

Cited by 471 publications

(335 citation statements)

References 41 publications

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“…Although NtACP lacks such an RGD sequence, there is an exposed Lys 144 -Thr 145 -Asp 146 (KTD) motif at the top end of domain 1. The KTD motif of NtACP is part of the G-I loop that structural and topological alignment procedures have identified as analogous to the loop containing the RGD motif of FnIII10 (35,40). Although integrins generally bind RGD sequences, several proteins have been shown to bind a number of related motifs, such as KTS (42,43), MLD (44), or MGD(W) (45) of disintegrins obtustatin, EC3, and EMF-10, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Distances reported are measured between C ␣ . Residues (RG)Asp 1495 (D1495), Asp 1373 (D1373), and Arg 1379 (D1379) of FnIII are known to be required for integrin binding (35,40,50). Residues Asp 911 (D911) and Asp 811 (D811) of Yersinia Inv497 are known to be involved in integrin binding (54 -56,71) and residue Arg 883 (R883) has been proposed as a structural analogue of Arg 1379 (R1379) of FnIII based on interresidue distances (51).…”

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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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 15N NOE values expected for isotropic motion of a protein with correlation time 7 ns are 0.79 at 500 MHz and 0.81 at 600 MHz). Loops between secondary-structure elements often have a high intrinsic mobility and their backbone amides show correspondingly low "N NOE values (e.g., Main et al, 1992). Figure 8 shows the NOE profide against the sequence both for the apo and holo proteins at 2 different 'H frequencies.…”

Section: Dynamic Behaviormentioning

confidence: 99%

Phosphopeptide binding to the N‐terminal SH2 domain of the p85α subunit of PI 3′‐kinase: A heteronuclear NMR study

et al. 1994

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The N-terminal src-homology 2 domain of the p85a subunit of phosphatidylinositol 3' kinase (SH2-N) binds specifically to phosphotyrosine-containing sequences. Notably, it recognizes phosphorylated Tyr 75 1 within the kinase insert of the cytoplasmic domain of the activated OPDGF receptor. A titration of a synthetic 12-residue phosphopeptide (ESVDY*VPMLDMK) into a solution of the SH2-N domain was monitored using heteronuclear 2D and 3D NMR spectroscopy. 2D-( "N-IH) heteronuclear single-quantum correlation (HSQC) experiments were performed at each point of the titration to follow changes in both I5N and ' H chemical shifts in NH groups. When mapped onto the solution structure of the SH2-N domain, these changes indicate a peptide-binding surface on the protein. Line shape analysis of ID profiles of individual ( "N-'H )-HSQC peaks at each point of the titration suggests a kinetic exchange model involving at least 2 steps. To characterize changes in the internal dynamics of the domain, the magnitude of the ( "N-IH J heteronuclear NOE for the backbone amide of each residue was determined for the SH2-N domain with and without bound peptide. These data indicate that, on a nanosecond timescale, there is no significant change in the mobility of either loops or regions of secondary structure. A mode of peptide binding that involves little conformational change except in the residues directly involved in the 2 binding pockets of the p85a SH2-N domain is suggested by this study.

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“…The flexible polypeptide linkage between Ig modules in antibody molecules permits a range of motion between domains and this flexibility relates directly to functional activity. It has been noted that FNIII and Ig modules have a similar overall structure (Main et al, 1992;Ely et al, 1995). It follows that the linkage patterns of FNIII and Ig modules may also be similar.…”

Section: Discussionmentioning

confidence: 95%

Conformational flexibility and crystallization of tandemly linked type III modules of human fibronectin

Lombardo

Wang

et al. 1996

Protein Science

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Abstract:Fibronectin is a large cell adhesion molecule that is composed of several functional domains. The cell-binding domain that binds to cell surface integrins consists of repeated homologous type 111 modules. In this study, recombinant fragments from the cell-binding domain of human fibronectin that participate in a newly characterized fibronectin-fibronectin interaction with FNIII I were crystallized. In each case, the crystals had more than one fibronectin fragment in the asymmetric unit. Crystals of F N I I I l o~l , grew in the space group C2 with a = 117.1 A, b = 38.6 A, c = 80.6 A, /3 = 97.2", and two molecules in the asymmetric unit.These crystals diffracted to 2.5 8, resolution. Fragment FNIII,-, and a shorter fragment, FNIIIx-,o, crystallized in hexagonal space groups with large unit cells and two to four molecules per asymmetric unit. Even very large crystals of these fragments did not diffract beyond 4 A. The crystal packing for this collection of fibronectin fragments suggests conformational flexibility between linked type 111 modules. The functional relevance of this flexibility for elongated versus compact models of the cell-binding domain of fibronectin is discussed.

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The three-dimensional structure of the tenth type III module of fibronectin: An insight into RGD-mediated interactions

Cited by 471 publications

References 41 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

Phosphopeptide binding to the N‐terminal SH2 domain of the p85α subunit of PI 3′‐kinase: A heteronuclear NMR study

Conformational flexibility and crystallization of tandemly linked type III modules of human fibronectin

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