RESUMO
Mycobacterium tuberculosis H37Rv is an intracellular pathogen responsible for causing tuberculosis in humans. The M. tuberculosis genome has been shown to contain a very large and unique family of PE proteins made of two sub-families: PE-only and PE_PGRS proteins. These two subtypes of proteins play a crucial role in the pathogenesis of the microbe. However, despite numerous investigations, the role of these proteins in disease development remains obscure. In this study, sequence analysis with a search for short conserved motifs revealed a conserved tetra-peptide motif DEVS/DXXS at the PE domain of almost every PE-only and PE_PGRS protein. The motif was found at a distance of 43-46 amino acids from the N-terminal of PE_PGRS proteins, and at a distance of between 35 and 82 amino acids of the PE-only proteins. As phosphorylation of the serine residue of this tetra-peptide could yield a motif similar to the caspase-3 binding recognition sequence DEVD/E, the region from a representative PE_PGRS protein (PE_PGRS45) was docked to human caspase-3. Strong interactions of only the protein containing the phosphorylated motif (DEVpS/DXXpS) to caspase-3 were observed. This suggested that the conserved DEVS/DXXS motif could have evolved for phosphorylation and subsequent recognition by caspase-3. These findings have important implications in unravelling the role of these PE proteins in mycobacterial infection.
Assuntos
Proteínas de Bactérias/genética , Caspase 3/genética , Mycobacterium tuberculosis/genética , Tuberculose/genética , Fatores de Virulência/genética , Motivos de Aminoácidos/genética , Sequência de Aminoácidos/genética , Sequência Conservada/genética , Genoma Bacteriano/genética , Interações Hospedeiro-Patógeno/genética , Humanos , Mycobacterium tuberculosis/patogenicidade , Peptídeos/genética , Alinhamento de Sequência/métodos , Tuberculose/microbiologia , Tuberculose/patologiaRESUMO
The PE_PGRS family of proteins unique to mycobacteria is demonstrated to contain multiple calcium-binding and glycine-rich sequence motifs GGXGXD/NXUX. This sequence repeat constitutes a calcium-binding parallel beta-roll or parallel beta-helix structure and is found in RTX toxins secreted by many Gram-negative bacteria. It is predicted that the highly homologous PE PGRS proteins containing multiple copies of the nona-peptide motif could fold into similar calcium-binding structures. The implication of the predicted calcium-binding property of PE PGRS proteins in the light of macrophage-pathogen interaction and pathogenesis is presented.
Assuntos
Antígenos de Bactérias/química , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mycobacterium tuberculosis/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Sequência de Bases , Sítios de Ligação/genética , Cálcio/metabolismo , DNA Bacteriano/genética , Proteínas de Membrana/genética , Modelos Moleculares , Dados de Sequência Molecular , Mycobacterium tuberculosis/genética , Estrutura Secundária de ProteínaRESUMO
Structural genomics, the large-scale determination of protein structures, promises to provide a broad structural foundation for drug discovery. The tuberculosis (TB) Structural Genomics Consortium is devoted to encouraging, coordinating, and facilitating the determination of structures of proteins from Mycobacterium tuberculosis and hopes to determine 400 TB protein structures over 5 years. The Consortium has determined structures of 28 proteins from TB to date. These protein structures are already providing a basis for drug discovery efforts.