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bioRxiv · 10.64898/2026.07.21.739776

A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export

Kumar, P.·Hyon, P. A.·Nixon, R.·Bullington, A. V.·Payne, C. A.·Lindberg, I.·Kober, D. L.
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Abstract

Prohormone convertase 1/3 (PC1/3, encoded by PCSK1) is a serine protease expressed in neuroendocrine cells that is required to produce insulin, glucagon-like peptide-1, adrenocorticotrophic hormone, and other peptide hormones. PC1/3 is synthesized as the zymogen proPC1/3, which undergoes autocatalytic maturation in the endoplasmic reticulum (ER) before trafficking to secretory granules. However, how autocatalytic maturation licenses the ER exit of PC1/3 remains unknown. Here, we determined the structure of an immature, catalytically inactive human proPC1/3S382A, which exits the ER as a domain-swapped homodimer. This domain-swapped conformation allows proPC1/3S382A to complete a conserved calcium pocket normally formed after autocatalysis and thereby become competent for ER exit. By defining this calcium pocket as a conformational checkpoint for ER export, our findings provide insights into the maturation of PC1/3 which may apply broadly to the PCSK family. Finally, our structure provides explanations for the functional consequences of many deleterious PCSK1 mutations.

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Kumar, P., Hyon, P. A., Nixon, R., Bullington, A. V., Payne, C. A., Lindberg, I., Kober, D. L.. 2026-07-22. A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export. https://doi.org/10.64898/2026.07.21.739776

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