Planar cell polarity (PCP) signaling controls a number of morphogenetic processes including convergent extension during gastrulation and neural tube formation. Defects in this pathway cause neural tube defects (NTD), the most common malformations of the central nervous system. The Looptail (Lp) mutant mouse was the first mammalian mutant implicating a PCP gene (Vangl2) in the pathogenesis of NTD. We report on a novel chemically induced mutant allele at Vangl2 called Curly Bob that causes a missense mutation p.Ile268Asn (I268N) in the Vangl2 protein. This mutant segregates in a semi-dominant fashion with heterozygote mice displaying a looped tail appearance, bobbing head, and a circling behavior. Homozygote mutant embryos suffer from a severe form of NTD called craniorachischisis, severe PCP defects in the inner hair cells of the cochlea and posterior cristae, and display a distinct defect in retinal axon guidance. This mutant genetically interacts with the Lp allele (Vangl2S464N) in neural tube development and inner ear hair cell polarity. The Vangl2I268N protein variant is expressed at very low levels in affected neural and retinal tissues of mutant homozygote embryos. Biochemical studies show that Vangl2I268N exhibits impaired targeting to the plasma membrane and accumulates in the endoplasmic reticulum. The Vangl2I268N variant no longer physically interacts with its PCP partner DVL3 and has a reduced protein half-life. This mutant provides an important model for dissecting the role of Vangl2 in the development of the neural tube, establishment of polarity of sensory cells of the auditory and vestibular systems, and retinal axon guidance.
Summary In order to study the physiological role of aminopeptidase A(APA), several α-mercapto-β-amino acyl dipeptides were synthesized
to obtain compounds having a high affinity for APA and a high selectivity versus aminopeptidase N (APN). Sulfornamide and
carboxylate moieties which have been shown to be recognized by the S1 subsite of the enzyme were introduced on the side chain of the α-mercapto-β-amino acyl sub-unit, the latter being coupled
to dipeptides optimized to interact with the S'1 and S'2 subsites by means of combinatorial chemistry. Good affinities (16nM) were obtained, the selectivity factors being up to 160-fold
versus APN. 相似文献
Summary The light chain of tetanus neurotoxin (TeNTL chain) has been shown to be endowed with zine endopeptidase activity, selectively
directed towards the Gln76-Phe77 bond of synaptobrevin, a vesicle-associated membrane protein critically involved in neuroexocytosis. In previous reports,
truncations at the NH2- and COOH-terminus of synaptobrevin have shown that the sequence 39–88 of synaptobrevin is the minimum substrate of TeNT,
suggesting either the requirement of a well-defined three-dimensional structure of synaptobrevin or a role in the mechanism
of substrate hydrolysis for residues distal from the cleavage site. In this study, the addition of NH2- and COOH-terminal peptides of synaptobrevin, S 27–55 (S1) and S 82–93 (S2), to the synaptobrevin fragment S 56–81 allowed the cleavage of this latter peptide by TeNT to occur. This appears to result
from an activation process mediated by the simultaneous binding of S1 and S2 with complementary sites present on TeNT as shown by surface plasmon resonance experiments. All these results favor an exosite-controlled
hydrolysis of synaptobrevin by TeNT probably involving a conformational change of the toxin. This could accound for the high
degree of substrate specificity of TeNT and, probably, botulinum neurotoxins. 相似文献
New neprilysin inhibitors containing an α-mercaptoketone HSC(R1R2)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S1, S1′ or S2′ domain of the enzyme and the nature of the substituents R1, R2 of the mercaptoketone group. Introduction of a cyclohexyl chain in R1, R2 position and a (3-thiophen)benzyl group in position R3 (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2 ± 0.3 nM. This result suggests that this new inhibitor interacts within the S1, S1′ domain of NEP allowing a pentacoordination of the catalytic Zn2+ ion by the mercaptoketone moiety. 相似文献
Robbing and bartering (RB) is a behavioral practice anecdotally reported in free-ranging commensal macaques. It usually occurs in two steps: after taking inedible objects (e.g., glasses) from humans, the macaques appear to use them as tokens, returning them to humans in exchange for food. While extensively studied in captivity, our research is the first to investigate the object/food exchange between humans and primates in a natural setting. During a 4-month study in 2010, we used both focal and event sampling to record 201 RB events in a population of long-tailed macaques (Macaca fascicularis), including four neighboring groups ranging freely around Uluwatu Temple, Bali (Indonesia). In each group, we documented the RB frequency, prevalence and outcome, and tested the underpinning anthropogenic and demographic determinants. In line with the environmental opportunity hypothesis, we found a positive qualitative relation at the group level between time spent in tourist zones and RB frequency or prevalence. For two of the four groups, RB events were significantly more frequent when humans were more present in the environment. We also found qualitative partial support for the male-biased sex ratio hypothesis [i.e., RB was more frequent and prevalent in groups with higher ratios of (sub)adult males], whereas the group density hypothesis was not supported. This preliminary study showed that RB is a spontaneous, customary (in some groups), and enduring population-specific practice characterized by intergroup variation in Balinese macaques. As such, RB is a candidate for a new behavioral tradition in this species. 相似文献