An Amino-Acid Position at the Crossroads of Evolution of Protein Function: antibiotic sensor domain of BlaR1 protein from staphylococcus aureus versus class d -lactamases

• Autores: Kumarasiri, Malika; Llarrull, Leticia Irene; Borbulevych, Oleg; Fishovitz, Jennifer; Lastochkin, Elena; Baker, Brian M.; Mobashery, Shahriar
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Staphylococcus aureus; Beta-lactam resistance; BlaR1
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

The integral membrane protein BlaR1 of Staphylococcus aureus senses the presence of beta-lactam antibiotics in the milieu and transduces the information to its cytoplasmic side, where its activity unleashes the expression of a set of genes, including that for BlaR1 itself, which manifest the antibioticresistant phenotype. The x-ray structure of the sensor domain of this protein exhibits an uncanny similarity to those of the class D beta-lactamases. The former is a membranebound receptor/sensor for the beta-lactam antibiotics, devoid of catalytic competence for substrate turnover, whereas the latter are soluble periplasmic enzymes in Gram-negative bacteria with avid ability for beta-lactam turnover. The two are clearly related to each other from an evolutionary point of view. However, the high resolution x-ray structures for both by themselves do not reveal why one is a receptor and the other an enzyme. It is documented herein that a single amino acid change at position 439 of the BlaR1 protein is sufficient to endow the receptor/sensor protein with modest turnover ability for cephalosporins as substrates. The x-ray structure for this mutant protein and the dynamics simulations revealed how a hydrolytic water molecule may sequester itself in the antibiotic-binding site to enable hydrolysis of the acylated species. These studies document how the nature of the residue at position 439 is critical for the fate of the protein in imparting unique functions on the same molecular template, to result in one as a receptor and in another as a catalyst.
Fil: Kumarasiri, Malika. University of Notre Dame-Indiana; Estados Unidos
Fil: Llarrull, Leticia Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Notre Dame-Indiana; Estados Unidos
Fil: Borbulevych, Oleg. University of Notre Dame-Indiana; Estados Unidos
Fil: Fishovitz, Jennifer. University of Notre Dame-Indiana; Estados Unidos
Fil: Lastochkin, Elena. University of Notre Dame-Indiana; Estados Unidos
Fil: Baker, Brian M.. University of Notre Dame-Indiana; Estados Unidos
Fil: Mobashery, Shahriar. University of Notre Dame-Indiana; Estados Unidos