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1.
Biophys J ; 123(8): 1006-1014, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38486451

RESUMEN

Plasma membrane damage occurs in healthy cells and more frequently in cancer cells where high growth rates and metastasis result in frequent membrane damage. The annexin family of proteins plays a key role in membrane repair. Annexins are recruited at the membrane injury site by Ca+2 and repair the damaged membrane in concert with several other proteins. Annexin A4 (ANXA4) and ANXA5 form trimers at the bilayer surface, and previous simulations show that the trimers induce high local negative membrane curvature on a flat bilayer. The membrane-curvature-inducing property of ANXA5 is presumed to be vital to the membrane repair mechanism. A previously proposed descriptive model hypothesizes that ANXA5-mediated curvature force is utilized at the free edge of the membrane at a wound site to pull the wound edges together, resulting in the formation of a "neck"-shaped structure, which, when combined with a constriction force exerted by ANXA6, leads to membrane repair. The molecular details and mechanisms of repair remain unknown, in part because the membrane edge is a transient structure that is difficult to investigate both experimentally and computationally. For the first time, we investigate the impact of ANXA5 near a membrane edge, which is modeled by a bicelle under periodic boundary conditions. ANXA5 trimers induce local curvature on the membrane leading to global bending of the bicelle. The global curvature depends on the density of annexins on the bicelle, and the curvature increases with the ANXA5 concentration until it reaches a plateau. The simulations suggest that not only do annexins induce local membrane curvature, but they can change the overall shape of a free-standing membrane. We also demonstrate that ANXA5 trimers reduce the rate of phosphatidylserine lipid diffusion from the cytoplasmic to the exoplasmic leaflet along the edge of the bicelle. In this way, membrane-bound annexins can potentially delay the apoptotic signal triggered by the presence of phosphatidylserine lipids in the outer leaflet, thus biding time for repair of the membrane hole. Our findings provide new insights into the role of ANXA5 at the edges of the membrane (the injury site) and support the curvature-constriction model of membrane repair.


Asunto(s)
Anexinas , Fosfatidilserinas , Anexina A5/análisis , Anexina A5/metabolismo , Fosfatidilserinas/metabolismo , Membrana Celular/metabolismo , Anexinas/análisis , Anexinas/química , Anexinas/metabolismo , Membranas/metabolismo
2.
Mol Cell ; 81(19): 3934-3948.e11, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34388369

RESUMEN

The signal peptidase complex (SPC) is an essential membrane complex in the endoplasmic reticulum (ER), where it removes signal peptides (SPs) from a large variety of secretory pre-proteins with exquisite specificity. Although the determinants of this process have been established empirically, the molecular details of SP recognition and removal remain elusive. Here, we show that the human SPC exists in two functional paralogs with distinct proteolytic subunits. We determined the atomic structures of both paralogs using electron cryo-microscopy and structural proteomics. The active site is formed by a catalytic triad and abuts the ER membrane, where a transmembrane window collectively formed by all subunits locally thins the bilayer. Molecular dynamics simulations indicate that this unique architecture generates specificity for SPs based on the length of their hydrophobic segments.


Asunto(s)
Retículo Endoplásmico/enzimología , Péptido Hidrolasas/metabolismo , Señales de Clasificación de Proteína , Serina Endopeptidasas/metabolismo , Células A549 , Dominio Catalítico , Microscopía por Crioelectrón , Células HEK293 , Células Hep G2 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Simulación de Dinámica Molecular , Péptido Hidrolasas/química , Péptido Hidrolasas/genética , Proteómica , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Relación Estructura-Actividad , Especificidad por Sustrato , Espectrometría de Masas en Tándem , Células U937
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