A model for collagen secretion by intercompartmental continuities.

Newly synthesized secretory proteins are exported from the endoplasmic reticulum (ER) at specialized subcompartments called exit sites (ERES). Cargoes like procollagen are too large for export by the standard COPII-coated vesicle of 60 nm average diameter. We have previously suggested that procollagen is transported from the ER to the next secretory organelle, the ER-Golgi intermediate compartment (ERGIC), in TANGO1-dependent interorganelle tunnels. In the theoretical model presented here, we suggest that intrinsically disordered domains of TANGO1 in the ER lumen induce an entropic contraction, which exerts a force that draws procollagen toward the ERES. Within this framework, molecular gradients of pH and/or HSP47 between the ER and ERGIC create a force in the order of tens of femto-Newtons. This force is substantial enough to propel procollagen from the ER at a speed of approximately 1 nm · s-1. This calculated speed and the quantities of collagen secreted are similar to its observed physiological secretion rate in fibroblasts, consistent with the proposal that ER export is the rate-limiting step for procollagen secretion. Hence, the mechanism we propose is theoretically adequate to explain how cells can utilize molecular gradients and export procollagens at a rate commensurate with physiological needs.

The beginning and the end of SNARE-induced membrane fusion.

Membrane fusion is not a spontaneous process. Physiologically, the formation of coiled-coil protein complexes, the SNAREpins, bridges the membrane of a vesicle and a target membrane, brings them in close contact, and provides the energy necessary for their fusion. In this review, we utilize results from in vitro experiments and simple physics and chemistry models to dissect the kinetics and energetics of the fusion process from the encounter of the two membranes to the full expansion of a fusion pore. We find three main energy barriers that oppose the fusion process: SNAREpin initiation, fusion pore opening, and expansion. SNAREpin initiation is inherent to the proteins and makes in vitro fusion kinetic experiments rather slow. The kinetics are physiologically accelerated by effectors. The energy barriers that precede pore opening and pore expansion can be overcome by several SNAREpins acting in concert.

Electrochemical TEMPO-Catalyzed Oxidative Ugi-Type Reaction.

Oxidative isocyanide-based multicomponent reactions (oxidative IMCRs) are very useful tools for the rapid construction of molecular diversity starting from readily available and stable substrates. Despite all their benefits, such multicomponent reactions are underdeveloped and strictly limited to 3-component processes. Indeed, in the presence of several reaction partners, the oxidation event needs to be rigorously chemoselective, which becomes incredibly more intricate as the number of reactive components increases. Nonetheless, we could overcome this significant pitfall and reach the first oxidative Ugi-type 4-IMCR by capitalizing on a very mild and green TEMPO-catalyzed electro-oxidation process. Employing alcohols as aldehyde surrogates and in the notable absence of any supporting electrolyte, this transformation proved to be extremely chemoselective in the presence of an amine and was compatible with a wide range of alcohols, amines, isocyanides, and carboxylic acids.