Structural snapshots of hyaluronan formation reveal principles of length control and secretion

Abstract

Hyaluronan (HA) is an essential component of the vertebrate extracellular matrix. It is a heteropolysaccharide of alternating N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) units reaching several megadaltons in healthy tissues. HA is synthesized and secreted in a coupled reaction by HA-synthase (HAS). Here, structural snapshots of HAS provide important insights into HA biosynthesis, from substrate recognition to HA elongation and translocation. We reveal a loop insertion mechanism for substrate binding, monitor the extension of a GlcNAc primer with GlcA, and capture the opening of a secretion channel that coordinates a nascent HA polymer. Further, we identify HA-interacting residues that control HA product lengths. Integrating structural and biochemical analyses, we propose a mechanism for HA length control based on finely tuned enzymatic processivity and catalytic rates.