Specificity and evolvability in eukaryotic protein interaction networks

Progress in uncovering the protein interaction networks of several species has led to questions of what underlying principles might govern their organization. Few studies have tried to determine the impact of protein interaction network evolution on the observed physiological differences between species. Using comparative genomics and structural information, we show here that eukaryotic species have rewired their interactomes at a fast rate of approximately 10⁻⁵ interactions changed per protein pair, per million years of divergence. For Homo sapiens this corresponds to 10³ interactions changed per million years. Additionally we find that the specificity of binding strongly determines the interaction turnover and that different biological processes show significantly different link dynamics. In particular, human proteins involved in immune response, transport, and establishment of localization show signs of positive selection for change of interactions. Our analysis suggests that a small degree of molecular divergence can give rise to important changes at the network level. We propose that the power law distribution observed in protein interaction networks could be partly explained by the cell's requirement for different degrees of protein binding specificity.     

Karyotypic evolution and phylogeny of Mexican Passalidae (Coleoptera: Polyphaga: Scarabaeoidea)

The chromosomes of 26 taxa from Mexico of the tribes Passalini (three species) and Proculini (23 species) have been studied, increasing the karyotypically known species of the family Passalidae to 56. Karyotypic dynamism is high since the diploid number varies from 18 to 44 in the tribe Proculini. and from 25 to 31 in the tribe Passalini. In addition, supernumerary chromosomes, chromosome heteromorphism, translocations and possible sex multivalents have been found. These results contrast with the numerical conservatism found in related families of the superfamily Scarabaeoidea. However, both tribes are conservative with regard to sex determination, as all species of Proculini have male XY chromosomes whereas species of the Passalini have male XO chromosomes. It is postulated that differences in patterns shown by these two tribes are mainly due to population structure, because many species of Proculini are endemic to restricted areas of Meso and South America, favouring the settlement of karyotypic changes, whereas species of Passalini are distributed over large areas in the lowlands. It is also postulated that the ancestral karyotypic formula of the family is close to 12–14 pairs of autosomes although the ancestral male sex determination may be either XY or XO. At present only a weak relationship between morphological and karyotypic evolution has been found, which together with the marked numerical variability found within and between genera make it difficult to obtain phylogenetic conclusions from karyotypic results.     

Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.

Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases.     

Influence of infection intensity on predilection sites in swine trichinellosis.

The muscular distribution of Trichinella spiralis or T. britovi was studied by digestion in 59 experimentally infected pigs and seven wild boars. Crus muscle was the predilection site in 89.3% of 28 heavily infected swine with 146-3634 larvae per gram (lpg), but in 51.6% of middle to light infections (0.005-59 lpg) the basis of the tongue showed higher larval densities than the crus muscle. The basis of the tongue was also the predilection site in 71.4% of wild boars. Highest counts in other muscles were found only in lightly infected pigs. The influence of intensity of infection, host species, and Trichinella species on muscle distribution is discussed.     

Circadian and circannual variation of the carrageenin inflammatory effect in rat

The circadian variation of edema produced by carrageenin (carr.) administration into plantar tissue was studied in rats kept under a 12 light - 12 dark regimen. Three doses were used (125, 250 and 500 micrograms per rat) injected at different time (02.00, 08,00, 14.00 and 20.00 h). With the high doses, the level of edema for the four hour period after carr. administration was similar whatever the hour of injection. In contrast, with the lower dose (125 micrograms) a circadian rhythm in the intensity of the edema produced was observed, showing a maximum of susceptibility during the light span. Repetitive experiments performed at different periods of the year validated this finding. Comparing mean mesors, analysis of this data showed two distinct levels of inflammation, with the lower level observed in autumn and winter indicating evidence for a circannual variability.     

Examination of the secondary structure of the kringle 4 domain of human plasminogen

The structure of a small region of human plasminogen (F4), consisting of amino acid residues Val354-Ala439 and containing its kringle 4 (K4) domain (residues Cys357-Cys434), has been predicted from Chou-Fasman calculations and hydropathy profiles, and compared to circular dichroism (CD) measurements on the isolated fragment. Calculations, by the Chou-Fasman method, of the probabilities of various types of secondary structures that exist in this region reveal that no helical structures are present. Of the total of 86 amino acid residues present in this K4-containing peptide region, 37% can adopt conformations of beta-pleated sheets, 48% of the amino acids can exist in beta-turns, and 15% of the residues can be present as coils. The structure of F4 in dilute aqueous solution has been experimentally evaluated by CD measurements. At pH = 7.4, in dilute salt solutions, a total of 64% beta-structures, 30% beta-turns, and 6% coiled structures is estimated to be present in this peptide region. Consideration of the marginal stability of many of the conformational regions of F4, as predicted by Chou-Fasman calculations, suggests that secondary structural flexibility is present in this fragment, which could result in ready adoption of new conformations. The hydropathy profile of F4 has been determined and suggests that this polypeptide is highly hydrophilic, especially in the regions of residues His387-Tyr396 and Cys406-Lys413. Thus, it appears as though a large portion of the surface of F4 can be exposed to solvent in its native conformation.