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bioRxiv · 10.1101/2023.05.11.540447

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

Gorniak, I.·Stephens, Z.·Erramilli, S.·Gawda, T.·Kossiakoff, A.·Zimmer, J.
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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.

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Gorniak, I., Stephens, Z., Erramilli, S., Gawda, T., Kossiakoff, A., Zimmer, J.. 2023-05-12. Structural snapshots of hyaluronan formation reveal principles of length control and secretion. https://doi.org/10.1101/2023.05.11.540447

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