64 research outputs found
The Evolution of Mammalian Gene Families
Gene families are groups of homologous genes that are likely to have highly similar functions. Differences in family size due to lineage-specific gene duplication and gene loss may provide clues to the evolutionary forces that have shaped mammalian genomes. Here we analyze the gene families contained within the whole genomes of human, chimpanzee, mouse, rat, and dog. In total we find that more than half of the 9,990 families present in the mammalian common ancestor have either expanded or contracted along at least one lineage. Additionally, we find that a large number of families are completely lost from one or more mammalian genomes, and a similar number of gene families have arisen subsequent to the mammalian common ancestor. Along the lineage leading to modern humans we infer the gain of 689 genes and the loss of 86 genes since the split from chimpanzees, including changes likely driven by adaptive natural selection. Our results imply that humans and chimpanzees differ by at least 6% (1,418 of 22,000 genes) in their complement of genes, which stands in stark contrast to the oft-cited 1.5% difference between orthologous nucleotide sequences. This genomic “revolving door” of gene gain and loss represents a large number of genetic differences separating humans from our closest relatives
Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways
Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also
between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles,
while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi
apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics
of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main
routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder
content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups
contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some
of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more
disordered (,23%) than the other two, COPI (,9%) and COPII (,8%). We show that this structural phenomenon enhances
the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other
two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its
prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest
capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific
functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for
protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of
structural disorder in vesicle trafficking and suggest major roles for this structural property in shaping the differences of
evolutionary adaptability in the three routes
A Membrane Fusion Protein αSNAP Is a Novel Regulator of Epithelial Apical Junctions
Tight junctions (TJs) and adherens junctions (AJs) are key determinants of the structure and permeability of epithelial barriers. Although exocytic delivery to the cell surface is crucial for junctional assembly, little is known about the mechanisms controlling TJ and AJ exocytosis. This study was aimed at investigating whether a key mediator of exocytosis, soluble N-ethylmaleimide sensitive factor (NSF) attachment protein alpha (αSNAP), regulates epithelial junctions. αSNAP was enriched at apical junctions in SK-CO15 and T84 colonic epithelial cells and in normal human intestinal mucosa. siRNA-mediated knockdown of αSNAP inhibited AJ/TJ assembly and establishment of the paracellular barrier in SK-CO15 cells, which was accompanied by a significant down-regulation of p120-catenin and E-cadherin expression. A selective depletion of p120 catenin effectively disrupted AJ and TJ structure and compromised the epithelial barrier. However, overexpression of p120 catenin did not rescue the defects of junctional structure and permeability caused by αSNAP knockdown thereby suggesting the involvement of additional mechanisms. Such mechanisms did not depend on NSF functions or induction of cell death, but were associated with disruption of the Golgi complex and down-regulation of a Golgi-associated guanidine nucleotide exchange factor, GBF1. These findings suggest novel roles for αSNAP in promoting the formation of epithelial AJs and TJs by controlling Golgi-dependent expression and trafficking of junctional proteins
Arrangements of proteins at reconstituted synaptic vesicle fusion sites depend on membrane separation
Synaptic vesicle proteins, including N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), Synaptotagmin-1 and Complexin, are responsible for controlling the synchronised fusion of synaptic vesicles with the presynaptic plasma membrane in response to elevated cytosolic calcium levels. A range of structures of SNAREs and their regulatory proteins have been elucidated, but the exact organisation of these proteins at synaptic junction membranes remains elusive. Here, we have used cryoelectron tomography to investigate the arrangement of synaptic proteins in anin vitroreconstituted fusion system. We found that the separation between vesicle and target membranes strongly correlates with the organisation of protein complexes at junctions. At larger membrane separations, protein complexes assume a 'clustered' distribution at the docking site, inducing a protrusion in the target membrane. As the membrane separation decreases, protein complexes become displaced radially outwards and assume a 'ring-like' arrangement. Our findings indicate that docked vesicles can possess a wide range of protein complex numbers and be heterogeneous in their protein arrangements
Complexin arrests a pool of docked vesicles for fast Ca2+-dependent release
Regulated exocytosis requires that the assembly of the basic membrane fusion machinery is temporarily arrested. Synchronized membrane fusion is then caused by a specific trigger-a local rise of the Ca2+ concentration. Using reconstituted giant unilamellar vesicles (GUVs), we have analysed the role of complexin and membrane-anchored synaptotagmin 1 in arresting and synchronizing fusion by lipid-mixing and cryo-electron microscopy. We find that they mediate the formation and consumption of docked small unilamellar vesicles (SUVs) via the following sequence of events: Synaptotagmin 1 mediates v-SNARE-SUV docking to t-SNARE-GUVs in a Ca2+-independent manner. Complexin blocks vesicle consumption, causing accumulation of docked vesicles. Together with synaptotagmin 1, complexin synchronizes and stimulates rapid fusion of accumulated docked vesicles in response to physiological Ca2+ concentrations. Thus, the reconstituted assay resolves both the stimulatory and inhibitory function of complexin and mimics key aspects of synaptic vesicle fusion. The EMBO Journal (2012) 31, 3270-3281. doi:10.1038/emboj.2012.164; Published online 15 June 201
Interactions Between SNAP-25 and Synaptotagmin-1 Are Involved in Vesicle Priming, Clamping Spontaneous and Stimulating Evoked Neurotransmission
Silicon-organic hybrid (SOH) integration for low-power and high-speed signal generation
Silicon-organic hybrid (SOH) integration combines silicon photonic devices with electro-optic organic cladding materials. We demonstrate that SOH modulators can be used to generate advanced modulation formats with high symbol rates at low operating voltages and low energy consumption. Moreover, we show that the SOH approach can be extended to plasmonic waveguide structures, leading to the plasmonic-organic hybrid (POH) concept
Complexin-1 Enhances the On-Rate of Vesicle Docking via Simultaneous SNARE and Membrane Interactions
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