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Biomedical subjects

B Leader

Publications and source records attributed to B Leader.

5 recordsLinked to original sources
PubMed2000

Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major.

Protozoan parasites of the genus Leishmania undergo a complex life cycle involving transmission by biting sand flies and replication within mammalian macrophage phagolysosomes. A major component of the Leishmania surface coat is the glycosylphosphatidylinositol (GPI)-anchored polysaccharide called lipophosphoglycan (LPG). LPG has been proposed to play many roles in the infectious cycle, including protection against complement and oxidants, serving as the major ligand for macrophage adhesion, and as a key factor mitigating host responses by deactivation of macrophage signaling pathways. However, all structural domains of LPG are shared by other major surface or secretory products, providing a biochemical redundancy that compromises the ability of in vitro tests to establish whether LPG itself is a virulence factor. To study truly lpg(-) parasites, we generated Leishmania major lacking the gene LPG1 [encoding a putative galactofuranosyl (Gal(f)) transferase] by targeted gene disruption. The lpg1(-) parasites lacked LPG but contained normal levels of related glycoconjugates and GPI-anchored proteins. Infections of susceptible mice and macrophages in vitro showed that these lpg(-) Leishmania were highly attenuated. Significantly and in contrast to previous LPG mutants, reintroduction of LPG1 into the lpg(-) parasites restored virulence. Thus, genetic approaches allow dissection of the roles of this complex family of interrelated parasite virulence factors, and definitively establish the role of LPG itself as a parasite virulence factor. Because the lpg1(-) mutant continue to synthesize bulk GPI-anchored Gal(f)-containing glycolipids other than LPG, a second pathway distinct from the Golgi-associated LPG synthetic compartment must exist.

Animals↗
PubMed2000

Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system.

Formin-1 is the founding member of a family of genes of emerging biological and medical importance that share specific domains of homology, allowing them to be classified together as the formin homology proteins. Although deficiency mutations in formin-1 lead to profound developmental defects in limb and kidney formation, similar deficiency mutations in more distantly related members of this family (diaphanous and cappuccino in Drosophila and BNI1 in yeast) have ostensibly unrelated phenotypes. Here we describe murine and human formin-2 (Fmn2), a gene which bears a high degree of similarity to formin-1 and cappuccino. The mouse gene, which encodes a putative 1567-amino-acid open reading frame and maps to mouse Chromosome 1, is expressed almost exclusively in the developing and mature central nervous system. Expression begins at embryonic day 9. 5 in the developing spinal cord and brain structures and continues in neonatal and adult brain structures including the olfactory bulb, cortex, thalamus, hypothalamus, hippocampus and cerebellum. Human formin-2 has a similar expression pattern.

Adult↗
PubMed1998

Sequence determinants for regulated degradation of yeast 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

The degradation rate of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-R), a key enzyme of the mevalonate pathway, is regulated through a feedback mechanism by the mevalonate pathway. To discover the intrinsic determinants involved in the regulated degradation of the yeast HMG-R isozyme Hmg2p, we replaced small regions of the Hmg2p transmembrane domain with the corresponding regions from the other, stable yeast HMG-R isozyme Hmg1p. When the first 26 amino acids of Hmg2p were replaced with the same region from Hmg1p, Hmg2p was stabilized. The stability of this mutant was not due to mislocalization, but rather to an inability to be recognized for degradation. When amino acid residues 27-54 of Hmg2p were replaced with those from Hmg1p, the mutant was still degraded, but its degradation rate was poorly regulated. The degradation of this mutant was still dependent on the first 26 amino acid residues and on the function of the HRD genes. These mutants showed altered ubiquitination levels that were well correlated with their degradative phenotypes. Neither determinant was sufficient to impart regulated degradation to Hmg1p. These studies provide evidence that there are sequence determinants in Hmg2p necessary for degradation and optimal regulation, and that independent processes may be involved in Hmg2p degradation and its regulation.

Amino Acid Sequence↗