Multiple stable conformations account for reversible concentration-dependent oligomerization and autoinhibition of a metamorphic metallopeptidase.

Molecular plasticity controls enzymatic activity: the native fold of a protein in a given environment is normally unique and at a global free-energy minimum. Some proteins, however, spontaneously undergo substantial fold switching to reversibly transit between defined conformers, the "metamorphic" proteins. Here, we present a minimal metamorphic, selective, and specific caseinolytic metallopeptidase, selecase, which reversibly transits between several different states of defined three-dimensional structure, which are associated with loss of enzymatic activity due to autoinhibition.

Architecture and function of metallopeptidase catalytic domains.

The cleavage of peptide bonds by metallopeptidases (MPs) is essential for life. These ubiquitous enzymes participate in all major physiological processes, and so their deregulation leads to diseases ranging from cancer and metastasis, inflammation, and microbial infection to neurological insults and cardiovascular disorders. MPs cleave their substrates without a covalent intermediate in a single-step reaction involving a solvent molecule, a general base/acid, and a mono- or dinuclear catalytic metal site.

A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases.

In the search for structural models of integral-membrane metallopeptidases (MPs), we discovered three related proteins from thermophilic prokaryotes, which we grouped into a novel family called "minigluzincins." We determined the crystal structures of the zymogens of two of these (Pyrococcus abyssi proabylysin and Methanocaldococcus jannaschii projannalysin), which are soluble and, with ∼100 residues, constitute the shortest structurally characterized MPs to date. Despite relevant sequence and structural similarity, the structures revealed two unique mechanisms of latency maintenance through the C-terminal segments previously unseen in MPs as follows: intramolecular, through an extended tail, in proabylysin, and crosswise intermolecular, through a helix swap, in projannalysin.

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor.

Karilysin is the only metallopeptidase identified as a virulence factor in the odontopathogen Tannerella forsythia owing to its deleterious effect on the host immune response during bacterial infection. The very close structural and sequence-based similarity of its catalytic domain (Kly18) to matrix metalloproteinases suggests that karilysin was acquired by horizontal gene transfer from an animal host. Previous studies by phage display identified peptides with the consensus sequence XWFPXXXGGG (single-letter amino-acid codes; X represents any residue) as karilysin inhibitors with low-micromolar binding affinities.

The structure of the catalytic domain of Tannerella forsythia karilysin reveals it is a bacterial xenologue of animal matrix metalloproteinases.

Metallopeptidases (MPs) are among virulence factors secreted by pathogenic bacteria at the site of infection. One such pathogen is Tannerella forsythia, a member of the microbial consortium that causes peridontitis, arguably the most prevalent infective chronic inflammatory disease known to mankind. The only reported MP secreted by T.

Prediction of a new class of RNA recognition motif.

The observation that activation domains (AD) of procarboxypeptidases are rather long compared to the pro-regions of other zymogens raises the possibility that they could play additional roles apart from precluding enzymatic activity within the proenzyme and helping in its folding process. In the present work, we compared the overall pro-domain tertiary structure with several proteins belonging to the same fold in the structural classification of proteins (SCOP) database by using structure and sequence comparisons. The best score obtained was between the activation domain of human procarboxypeptidase A4 (ADA4h) and the human U1A protein from the U1 snRNP.

Influence of aggregation propensity and stability on amyloid fibril formation as studied by Fourier transform infrared spectroscopy and two-dimensional COS analysis.

Understanding the process of amyloidogenesis is important for the future treatment of misfolding-based diseases, such as Alzheimer's, spongiform encephalopathies, and other important disorders affecting humans. In this work, we have used one of the best-characterized models for folding and misfolding, the activation domain of human procarboxypeptidase A2 (ADA2h). The wild type (WT) and three mutants affecting the kinetics of aggregation have been studied by IR from the folded state at acidic pD to fibril formation, showing the disappearance of structured features prior to a dramatic increase in the magnitude of the amyloid-characteristic band upon temperature induction.