In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate.
The proprotein convertase PC5/6 cleaves protein precursors after basic amino acids and is essential for implantation in CD1/129/Sv/C57BL/6 mixed-background mice. Conditional inactivation of Pcsk5 in the epiblast but not in the extraembryonic tissue bypassed early embryonic lethality but resulted in death at birth. PC5/6-deficient embryos exhibited Gdf11-related phenotypes such as altered anteroposterior patterning with extra vertebrae and lack of tail and kidney agenesis. They also exhibited Gdf11-independent phenotypes, such as a smaller size, multiple hemorrhages, collapsed alveoli, and retarded ossification. In situ hybridization revealed overlapping PC5/6 and Gdf11 mRNA expression patterns. In vitro and ex vivo analyses showed that the selectivity of PC5/6 for Gdf11 essentially resides in the presence of a P1' Asn in the RSRR downward arrowN cleavage motif. This work identifies Gdf11 as a likely in vivo specific substrate of PC5/6 and opens the way to the identification of other key substrates of this convertase.
Essalmani
Rachid
R
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC, Canada.
Zaid
Ahmed
A
Marcinkiewicz
Jadwiga
J
Chamberland
Ann
A
Pasquato
Antonella
A
Seidah
Nabil G
NG
Prat
Annik
A
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055412:Growth Differentiation Factors; D048788:Growth and Development; D051379:Mice; D010641:Phenotype; D045702:Proprotein Convertase 5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013379:Substrate Specificity
D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D012333:RNA, Messenger; D045702:Proprotein Convertase 5; C473805:propeptide convertase 5, mouse