Impas 1 possesses endoproteolytic activity against multipass membrane protein substrate cleaving the presenilin 1 holoprotein

AbstractPresenilins (PS1 and PS2) are supposed to be unusual aspartic proteases and components of the γ-secretase complex regulating cleavage of type I proteins. Multiple mutations in PS1 are a major cause of familial early-onset Alzheimer’s disease (AD). We and others recently identified PS-related families of proteins (IMPAS/PSH/signal peptide peptidases (SPP)). The functions of these proteins are yet to be determined. We found that intramembrane protease-associated or intramembrane protease aspartic protein Impas 1 (IMP1)/SPP induces intramembranous cleavage of PS1 holoprotein in cultured cells coexpressing these proteins. Mutations in evolutionary invariant sites in hIMP1 or specific γ-secretase inhibitors abolish the hIMP1-mediated endoproteolysis of PS1. In contrast, neither AD-like mutations in hIMP1 nor in PS1 substrate abridge the PS1 cleavage. The data suggest that IMP1 is a bi-aspartic polytopic protease capable of cleaving transmembrane precursor proteins. These data, to our knowledge, are a first observation that a multipass transmembrane protein or the integral protease per se may be a primary substrate for an intramembranous proteolysis

Complete Mitochondrial Genome and Phylogeny of Pleistocene MammothMammuthus primigenius

Phylogenetic relationships between the extinct woolly mammoth(Mammuthus primigenius), and the Asian(Elephas maximus) and African savanna(Loxodonta africana) elephants remain unresolved. Here, we report the sequence of the complete mitochondrial genome (16,842 base pairs) of a woolly mammoth extracted from permafrost-preserved remains from the Pleistocene epoch—the oldest mitochondrial genome sequence determined to date. We demonstrate that well-preserved mitochondrial genome fragments, as long as ~1,600–1700 base pairs, can be retrieved from pre-Holocene remains of an extinct species. Phylogenetic reconstruction of the Elephantinae clade suggests thatM. primigenius andE. maximus are sister species that diverged soon after their common ancestor split from theL. africana lineage. Low nucleotide diversity found between independently determined mitochondrial genomic sequences of woolly mammoths separated geographically and in time suggests that north-eastern Siberia was occupied by a relatively homogeneous population ofM. primigenius throughout the late Pleistocene

Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH

The molecular mechanisms controlling human hair growth and scalp hair loss are poorly understood. By screening about 350,000 individuals in two populations from the Volga-Ural region of Russia, we identified a gene mutation in families who show an inherited form of hair loss and a hair growth defect. Affected individuals were homozygous for a deletion in the LIPH gene on chromosome 3q27, caused by short interspersed nuclear element-retrotransposon-mediated recombination. The LIPH gene is expressed in hair follicles and encodes a phospholipase called lipase H (alternatively known as membrane-associated phosphatidic acid-selective phospholipase A1alpha), an enzyme that regulates the production of bioactive lipids. These results suggest that lipase H participates in hair growth and development

The Right Back Leg of the Woolly Mammoth<i>(M. primigenius)</i> Found in Siberia

<p>The well-preserved mammoth body fragment with foot (33 × 36 cm), shin, and ankle-joint (the total length is ~88 cm) was found in the Enmynveem River valley (north-eastern Siberia, Chukotka). The tissue material (bones, muscles, and skin) had no visible marks of tissue damage by insects or other animals. Radiocarbon dating of the skin and muscle tissue determined that the mammoth lived 32,850 ± 900 y ago [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b012" target="_blank">12</a>].</p

Paenungulata Tree and Phylogenic Relationship of the Woolly Mammoth

<p>The analysis of complete mtDNA sequences placesM. primigenius withE. maximus on the tree. The Sirenia<i>(D. dugon)</i> and Hyracoidea<i>(P. capensis),</i> most closely related species among extant taxa to Elephantinae, were taken as outgroups. Bootstrap values and posterior probabilities were calculated using a Bayesian approach [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b029" target="_blank">29</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b031" target="_blank">31</a>] assuming a gamma distribution of the rates of evolution across sites with a General Time Reversible model (normal font), HKY model (bold), with a parsimony approach (italic), and by neighbor joining (italic and bold) [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040073#pbio-0040073-b028" target="_blank">28</a>]. The scale is 0.1 substitutions per site. The mitochondrial genomes of<i>M. primigenius, E. maximus A, E. maximus B, L. africana A, L. africana B, D. dugon,</i> andP. capensis were used in the analysis.</p

The Unusually Well-Preserved Mammoth DNA

<p>(A) Nuclei with DNA clearly detectable by DAPI staining in muscle cells of ~33,000-y-oldM. primigenius. (B) Total genomic DNA isolated from the mammoth muscle tissue (lane 1 is 1/10 dilution of the DNA on lane 2); control DNA from fresh human blood samples in lanes 3 and 4. (C) Examples of PCR products (~300–600 bp) for mammoth mitochondrial genome. (D) PCR amplification recovers long sequences for complete mitochondrial genes (1,317 bp<i>CytB</i> and 1,613 bp<i>ATP6</i> genes), but PCR of larger fragments (3,054 bp<i>ND5</i>) is failed.</p

Mitochondrial Genome of the Woolly MammothM. primigenius

<p>The complete mitochondrial genome was determined independently in two different laboratories using designs with multiple primers for overlapping PCR fragments ranged from ~325 to ~650 bp; the longer PCR fragments were also produced and sequenced. The overlapped PCR products used for sequencing and cloning are shown by the inner circle. Only PCR fragments produced from different pairs of primers are shown. Two genes,<i>ATP6</i> and<i>ND4L,</i> overlap with neighboring genes.</p