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1.
Elife ; 92020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32631487

RESUMO

γ-Secretase is a multi-subunit enzyme whose aberrant activity is associated with Alzheimer's disease and cancer. While its structure is atomically resolved, γ-secretase localization in the membrane in situ relies mostly on biochemical data. Here, we combined fluorescent tagging of γ-secretase subunits with super-resolution microscopy in fibroblasts. Structured illumination microscopy revealed single γ-secretase complexes with a monodisperse distribution and in a 1:1 stoichiometry of PSEN1 and nicastrin subunits. In living cells, sptPALM revealed PSEN1/γ-secretase mainly with directed motility and frequenting 'hotspots' or high track-density areas that are sensitive to γ-secretase inhibitors. We visualized γ-secretase association with substrates like amyloid precursor protein and N-cadherin, but not with its sheddases ADAM10 or BACE1 at the cell surface, arguing against pre-formed megadalton complexes. Nonetheless, in living cells PSEN1/γ-secretase transiently visits ADAM10 hotspots. Our results highlight the power of super-resolution microscopy for the study of γ-secretase distribution and dynamics in the membrane.


Assuntos
Secretases da Proteína Precursora do Amiloide/genética , Presenilina-1/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Fibroblastos , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Microscopia , Presenilina-1/metabolismo
2.
Cell ; 134(6): 945-55, 2008 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-18805088

RESUMO

Bacterial replication origins move towards opposite ends of the cell during DNA segregation. We have identified a proline-rich polar protein, PopZ, required to anchor the separated Caulobacter crescentus chromosome origins at the cell poles, a function that is essential for maintaining chromosome organization and normal cell division. PopZ interacts directly with the ParB protein bound to specific DNA sequences near the replication origin. As the origin/ParB complex is being replicated and moved across the cell, PopZ accumulates at the cell pole and tethers the origin in place upon arrival. The polar accumulation of PopZ occurs by a diffusion/capture mechanism that requires the MreB cytoskeleton. High molecular weight oligomers of PopZ assemble in vitro into a filamentous network with trimer junctions, suggesting that the PopZ network and ParB-bound DNA interact in an adhesive complex, fixing the chromosome origin at the cell pole.


Assuntos
Proteínas de Bactérias/metabolismo , Caulobacter crescentus/citologia , Caulobacter crescentus/metabolismo , Cromossomos Bacterianos/metabolismo , Origem de Replicação , Caulobacter crescentus/genética , Replicação do DNA
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