Bunel, LouisPincet, LancelotMalhotra, VivekRaote, IshierPincet, Frederic2024-02-142024-02-142024Bunel 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.23104041200027-8424http://hdl.handle.net/10230/59108Newly 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.application/pdfeng© Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1073/pnas.2310404120TANGO1CollagenEntropic ratchetpH gradientSecretioninfo:eu-repo/semantics/openAccess