α-macroglobulins are broad-spectrum endopeptidase inhibitors, which have to date been characterised from metazoans (vertebrates and invertebrates) and Gram-negative bacteria. Their structural and biochemical properties reveal two related modes of action: the "Venus flytrap" and the "snap-trap" mechanisms. In both cases, peptidases trigger a massive conformational rearrangement of α-macroglobulin after cutting in a highly flexible bait region, which results in their entrapment.
View Article and Find Full Text PDFPeptidases must be exquisitely regulated to prevent erroneous cleavage and one control is provided by protein inhibitors. These are usually specific for particular peptidases or families and sterically block the active-site cleft of target enzymes using lock-and-key mechanisms. In contrast, members of the +1400-residue multi-domain α2-macroglobulin inhibitor family (α2Ms) are directed against a broad spectrum of endopeptidases of disparate specificities and catalytic types, and they inhibit their targets without disturbing their active sites.
View Article and Find Full Text PDFI'm your Venus: the crystal structure of the human methylamine-induced form of α(2)-macroglobulin (α(2)M) shows its large central cavity can accommodate two medium-sized proteinases. Twelve major entrances provide access for small substrates to the cavity and the still-active trapped "prey". The structure unveils the molecular basis of the unique "venus flytrap" mechanism of α(2)M.
View Article and Find Full Text PDFHmrA is an antibiotic resistance factor of methicillin-resistant Staphylococcus aureus. Molecular analysis of this protein revealed that it is not a muramidase or β-lactamase but a nonspecific double-zinc endopeptidase consisting of a catalytic domain and an inserted oligomerization domain, which probably undergo a relative interdomain hinge rotation upon substrate binding. The active-site cleft is located at the domain interface.
View Article and Find Full Text PDFBiochim Biophys Acta
January 2010
Matrix metalloproteinases (MMPs) are zinc-dependent protein and peptide hydrolases. They have been almost exclusively studied in vertebrates and 23 paralogs are present in humans. They are widely involved in metabolism regulation through both extensive protein degradation and selective peptide-bond hydrolysis.
View Article and Find Full Text PDFHuman growth and development are conditioned by insulin-like growth factors (IGFs), which have also implications in pathology. Most IGF molecules are sequestered by IGF-binding proteins (IGFBPs) so that exertion of IGF activity requires disturbance of these complexes. This is achieved by proteolysis mediated by IGFBP proteases, among which the best characterised is human PAPP-A, the first member of the pappalysin family of metzincins.
View Article and Find Full Text PDFA/B-type metallocarboxypeptidases (MCPs) are among the most thoroughly studied proteolytic enzymes, and their catalytic mechanisms have been considered as prototypes even for several unrelated metalloprote(in)ase families. It has long been postulated that the nature of the side chains of at least five substrate residues, i.e.
View Article and Find Full Text PDFHuman pappalysin-1 is a multi-domain metalloprotease engaged in the homeostasis of insulin-like growth factors and the founding member of the pappalysin family within the metzincin clan of metalloproteases. We have recently identified an archaeal relative, ulilysin, encompassing only the protease domain. It is a 262-residue active protease with a novel 3D structure with two subdomains separated by an active-site cleft.
View Article and Find Full Text PDFJ Mol Biol
August 2006
Methicillin-resistant Staphylococcus aureus (MRSA) strains are responsible for most hospital-onset bacterial infections. Lately, they have become a major threat to the community through infections of skin, soft tissue and respiratory tract, and subsequent septicaemia or septic shock. MRSA strains are resistant to most beta-lactam antibiotics (BLAs) as a result of the biosynthesis of a penicillin-binding protein with low affinity for BLAs, called PBP2a, PBP2' or MecA.
View Article and Find Full Text PDFGlobalisation has entailed a massive increase in trade and human mobility facilitating the rapid spread of infectious agents, including those that are drug resistant. A particularly serious threat to human health is posed by methicillin-resistant staphylococcal strains which have acquired molecular mechanisms to evade the action of beta-lactam antibiotics (BLAs). Full expression of high-level methicillin resistance involves a complex network of molecules and depends primarily on sufficient expression of a penicillin-binding protein with low sensitivity towards BLAs.
View Article and Find Full Text PDFBacterial resistance to antibiotics poses a serious worldwide public health problem due to the high morbidity and mortality caused by infectious diseases. Most hospital-onset infections are associated with methicillin-resistant Staphylococcus aureus (MRSA) strains that have acquired multiple drug resistance to beta-lactam antibiotics. In a response to antimicrobial stress, nearly all clinical MRSA isolates produce beta-lactamase (BlaZ) and a penicillin-binding protein with low affinity for beta-lactam antibiotics (PBP2a, also known as PBP2' or MecA).
View Article and Find Full Text PDFMethicillin-resistant Staphylococcus aureus is the main cause of nosocomial and community-onset infections that affect millions of people worldwide. Some methicillin-resistant Staphylococcus aureus infections have become essentially untreatable by beta-lactams because of acquired molecular machineries enabling antibiotic resistance. Evasion from methicillin challenge is mainly achieved by the synthesis of a penicillin-binding protein of low affinity for antibiotics, MecA, that replaces regular penicillin-binding proteins in cell wall turnover when these have been inactivated by antibiotics.
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