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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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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