A model for collagen secretion by intercompartmental continuities

Bunel, Louis; Pincet, Lancelot; Malhotra, Vivek; Raote, Ishier; Pincet, Frederic

doi:http://dx.doi.org/10.1073/pnas.2310404120

A model for collagen secretion by intercompartmental continuities

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Bunel L, Pincet L, Malhotra V, Raote I, Pincet F. A model for collagen secretion by intercompartmental continuities. Proc Natl Acad Sci U S A. 2024 Jan 2;121(1):e2310404120. DOI: 10.1073/pnas.2310404120

Abstract

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.