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Pancreatic cancer incurs the worst survival rate of the major cancers. High levels of the protease matrix metalloproteinase-7 (MMP-7) in circulation correlate with poor prognosis and limited survival of patients. MMP-7 is required for a key path of pancreatic tumorigenesis in mice and is present throughout tumor progression. Enhancements to chemotherapies are needed for increasing the number of pancreatic tumors that can be removed and for preventing relapses after surgery. With these ends in mind, selective inhibition of MMP-7 may be worth investigation. An anti-MMP-7 monoclonal antibody was recently shown to increase the susceptibility of several pancreatic cancer cell lines to chemotherapeutics, increase their apoptosis, and decrease their migration. MMP-7 activities are most apparent at the surfaces of innate immune, epithelial, and tumor cells. Proteolytic shedding of multiple protein ectodomains by MMP-7 from such cell surfaces influence apoptosis, proliferation, migration, and invasion. These activities warrant targeting of MMP-7 selectively in pancreatic cancer and other tumors of mucosal epithelia. Competitive and non-competitive modes of MMP-7 inhibition are discussed. [ABSTRACT FROM AUTHOR]

Several studies are conducted to explain the mechanisms, structure, affinity and specificity of the phosphoprotein-binding FHA domains, which act as protein modules for switching signals in diverse biological pathways. The dynamics of these FHA domains is shown to be highly dependent on the phosphopeptide.

The first NMR mapping of the surface of a J domain recognizing a mammalian hsp70, the ATPase domain of Hsc70, is presented. T antigen is hypothesized to position Hsc70 for direct action upon an E2F bound to a pocket protein such as pRb, and this region binding with E2F1 is demonstrated to be an excellent substrate for Hsc70 in vitro, possibly because of an inherently unfolded region.

Solution structure of the complex between N-TIMP-1 in the matrix metalloproteinase (MMP)-3(deltaC) active site is similar to that of crystal structure of the complex, indicating that the crystalline orientation is not skewed and that the difference between crystal and solution structures is due to structural differences exhibited by the AB loops of TIMPs.

Asthma is prevalent in children and cats, and needs means of noninvasive diagnosis. We sought to distinguish noninvasively the differences in 53 cats before and soon after induction of allergic asthma, using NMR spectra of exhaled breath condensate (EBC). Statistical pattern recognition was improved considerably by preprocessing the spectra with probabilistic quotient normalization and glog transformation. Classification of the 106 preprocessed spectra by principal component analysis and partial least squares with discriminant analysis (PLS-DA) appears to be impaired by variances unrelated to eosinophilic asthma. By filtering out confounding variances, orthogonal signal correction (OSC) PLS-DA greatly improved the separation of the healthy and early asthmatic states, attaining 94% specificity and 94% sensitivity in predictions. OSC enhancement of multi-level PLS-DA boosted the specificity of the prediction to 100%. OSC-PLS-DA of the normalized spectra suggest the most promising biomarkers of allergic asthma in cats to include increased acetone, metabolite(s) with overlapped NMR peaks near 5.8 ppm, and a hydroxyphenyl-containing metabolite, as well as decreased phthalate. Acetone is elevated in the EBC of 74% of the cats with early asthma. The noninvasive detection of early experimental asthma, biomarkers in EBC, and metabolic perturbation invite further investigation of the diagnostic potential in humans. [ABSTRACT FROM AUTHOR]

How does matrix metalloproteinase-12 (MMP-12 or metalloelastase) degrade elastin with high specific activity? Nuclear magnetic resonance suggested soluble elastin covers surfaces of MMP-12 far from its active site. Two of these surfaces have been found, by mutagenesis guided by the BINDSIght approach, to affect degradation and affinity for elastin substrates but not a small peptide substrate. Main exosite 1 has been extended to Asp124 that binds calcium. Novel exosite 2 comprises residues from the II-III loop and β-strand I near the back of the catalytic domain. The high degree of exposure of these distal exosites may make them accessible to elastin made more flexible by partial hydrolysis. Importantly, the combination of one lesion each at exosites 1 and 2 and the active site decreased the catalytic competence toward soluble elastin by 13-18-fold to the level of MMP-3, homologue and poor elastase. Double-mutant cycle analysis of conservative mutations of Met156 (exosite 2) and either Asp124 (exosite 1) or Ile180 (active site) showed they had additive effects. Compared to polar substitutions observed in other MMPs, Met156 enhanced affinity and Ile180 the kcat for soluble elastin. Both residues detracted from the higher folding stability with polar mutations. This resembles the trend in enzymes of an inverse relationship between folding stability and activity. Restoring Asp124 from combination mutants enhanced the kcat for soluble elastin. In elastin degradation, exosites 1 and 2 contributed in a manner independent of each other and Ile180 at the active site, but with partial coupling to Ala182 near the active site. The concept of weak, separated interactions coalescing somewhat independently can be extended to this proteolytic digestion of a protein from fibrils. [ABSTRACT FROM AUTHOR]