Catálogo de publicaciones - revistas

<jats:p>Engagement of antigen and immunoglobulin receptors on hematopoietic cells is directly coupled to activation of nonreceptor protein tyrosine kinases (PTKs) that then phosphorylate critical intracellular substrates. In mast cells stimulated through the FcɛRI receptor, activation of several PTKs including Syk leads to degranulation and release of such mediators of the allergic response as histamine and serotonin. Regulation of Syk function occurred through interaction with the Cbl protein, itself a PTK substrate in this system. Overexpression of Cbl led to inhibition of Syk and suppression of serotonin release from mast cells, demonstrating its ability to inhibit a nonreceptor tyrosine kinase. Complex adaptor proteins such as Cbl can directly regulate the functions of the proteins they bind.</jats:p>

<jats:p> The crystal structure of the arabinose-binding and dimerization domain of the <jats:italic>Escherchia coli</jats:italic> gene regulatory protein AraC was determined in the presence and absence of <jats:sc>l</jats:sc> -arabinose. The 1.5 angstrom structure of the arabinose-bound molecule shows that the protein adopts an unusual fold, binding sugar within a β barrel and completely burying the arabinose with the amino-terminal arm of the protein. Dimer contacts in the presence of arabinose are mediated by an antiparallel coiled-coil. In the 2.8 angstrom structure of the uncomplexed protein, the amino-terminal arm is disordered, uncovering the sugar-binding pocket and allowing it to serve as an oligomerization interface. The ligand-gated oligomerization as seen in AraC provides the basis of a plausible mechanism for modulating the protein’s DNA-looping properties. </jats:p>

<jats:p> The severity of the malaria pandemic in the tropics is aggravated by the ongoing spread of parasite resistance to antimalarial drugs and mosquito resistance to insecticides. A strain of <jats:italic>Anopheles gambiae</jats:italic> , normally a major vector for human malaria in Africa, can encapsulate and kill the malaria parasites within a melanin-rich capsule in the mosquito midgut. Genetic mapping revealed one major and two minor quantitative trait loci (QTLs) for this encapsulation reaction. Understanding such antiparasite mechanisms in mosquitoes may lead to new strategies for malaria control. </jats:p>

<jats:p> The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesis <jats:italic>N</jats:italic> -butyldeoxynojirimycin, was evaluated in a mouse model of Tay-Sachs disease. When Tay-Sachs mice were treated with <jats:italic>N</jats:italic> -butyldeoxynojirimycin, the accumulation of G <jats:sub>M2</jats:sub> in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, limiting the biosynthesis of the substrate (G <jats:sub>M2</jats:sub> ) for the defective enzyme (β-hexosaminidase A) prevents GSL accumulation and the neuropathology associated with its lysosomal storage. </jats:p>

<jats:p> The crystal structure of the adenine nucleotide exchange factor GrpE in complex with the adenosine triphosphatase (ATPase) domain of <jats:italic>Escherichia coli</jats:italic> DnaK [heat shock protein 70 (Hsp70)] was determined at 2.8 angstrom resolution. A dimer of GrpE binds asymmetrically to a single molecule of DnaK. The structure of the nucleotide-free ATPase domain in complex with GrpE resembles closely that of the nucleotide-bound mammalian Hsp70 homolog, except for an outward rotation of one of the subdomains of the protein. This conformational change is not consistent with tight nucleotide binding. Two long α helices extend away from the GrpE dimer and suggest a role for GrpE in peptide release from DnaK. </jats:p>