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Unravelling the structure of the pneumococcal autolytic lysozyme.

ABSTRACT: The LytC lysozyme of Streptococcus pneumoniae forms part of the autolytic system of this important pathogen. This enzyme is composed of a C-terminal CM (catalytic module), belonging to the GH25 family of glycosyl hydrolases, and an N-terminal CBM (choline-binding module), made of eleven homologous repeats, that specifically recognizes the choline residues that are present in pneumococcal teichoic and lipoteichoic acids. This arrangement inverts the general assembly pattern of the major pneumococcal autolysin, LytA, and the lytic enzymes encoded by pneumococcal bacteriophages that place the CBM (made of six repeats) at the C-terminus. In the present paper, a three-dimensional model of LytC built by homology modelling of each module and consistent with spectroscopic and hydrodynamic studies is shown. In addition, the putative catalytic-pair residues are identified. Despite the inversion in the modular arrangement, LytC and the bacteriophage-encoded Cpl-1 lysozyme most probably adopt a similar global fold. However, the distinct choline-binding ability and their substrate-binding surfaces may reflect a divergent evolution directed by the different roles played by them in the host (LytC) or in the bacteriophage (Cpl-1). The tight binding of LytC to the pneumococcal envelope, mediated by the acquisition of additional choline-binding repeats, could facilitate the regulation of the potentially suicidal activity of this autolysin. In contrast, a looser attachment of Cpl-1 to the cell wall and the establishment of more favourable interactions between its highly negatively charged catalytic surface and the positively charged chains of pneumococcal murein could enhance the lytic activity of the parasite-encoded enzyme and therefore liberation of the phage progeny.

SUBMITTER: Monterroso B

PROVIDER: S-EPMC1237137 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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Unravelling the structure of the pneumococcal autolytic lysozyme.

Monterroso Begoña B López-Zumel Consuelo C García José L JL Sáiz José L JL García Pedro P Campillo Nuria E NE Menéndez Margarita M

The Biochemical journal 20051001 Pt 1

The LytC lysozyme of Streptococcus pneumoniae forms part of the autolytic system of this important pathogen. This enzyme is composed of a C-terminal CM (catalytic module), belonging to the GH25 family of glycosyl hydrolases, and an N-terminal CBM (choline-binding module), made of eleven homologous repeats, that specifically recognizes the choline residues that are present in pneumococcal teichoic and lipoteichoic acids. This arrangement inverts the general assembly pattern of the major pneumococ ...[more]

PMID: 15943581

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Project description:The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.

Project description:Recently we showed that the three-dimensional structure of proteins can be investigated from a network perspective, where the amino acid residues represent the nodes in the network and the noncovalent interactions between them are considered for the edge formation. In this study, the dynamical behavior of such networks is examined by considering the example of T4 lysozyme. The equilibrium dynamics and the process of unfolding are followed by simulating the protein at 300 K and at higher temperatures (400 K and 500 K), respectively. The snapshots of the protein structure from the simulations are represented as protein structure networks in which the strength of the noncovalent interactions is considered an important criterion in the construction of edges. The profiles of the network parameters, such as the degree distribution and the size of the largest cluster (giant component), were examined as a function of interaction strength at different temperatures. Similar profiles are seen at all the temperatures. However, the critical strength of interaction (Icritical) and the size of the largest cluster at all interaction strengths shift to lower values at 500 K. Further, the folding/unfolding transition is correlated with contacts evaluated at Icritical and with the composition of the top large clusters obtained at interaction strengths greater than Icritical. Finally, the results are compared with experiments, and predictions are made about the residues, which are important for stability and folding. To summarize, the network analysis presented in this work provides insights into the details of the changes occurring in the protein tertiary structure at the level of amino acid side-chain interactions, in both the equilibrium and the unfolding simulations. The method can also be employed as a valuable tool in the analysis of molecular dynamics simulation data, since it captures the details at a global level, which may elude conventional pairwise interaction analysis.

Dataset Information

Unravelling the structure of the pneumococcal autolytic lysozyme.

Publications

Unravelling the structure of the pneumococcal autolytic lysozyme.

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