Heparin nucleates and promotes tropoelastin coacervation through a transient interaction driven by domain 36

Elastin is the extracellular matrix (ECM) protein responsible for the elastic recoil property of certain tissues including the skin, arteries, and lung. Elastic fibre assembly begins with the coacervation of soluble monomeric tropoelastin and is driven by interactions with other ECM components such as glycosaminoglycans (GAGs). Previous research shows that GAG interactions can promote tropoelastin coacervation but lack structural and mechanistic details of this interaction. In this study, we describe the key interactions between tropoelastin and heparin using NMR spectroscopy and coacervation experiments. We propose a mechanism in which substoichiometric GAGs can act as a nucleating scaffold, primarily through transient multivalent interactions with domain 36 of tropoelastin, reducing the energetic barrier for coacervation. Our results provide the first detailed molecular view of tropoelastin-GAG interactions and support a role for negatively charged GAGs in modulating tropoelastin coacervation and thus initiating elastic fibre assembly.