Zymogen Activation and Subcellular Activity of Subtilisin Kexin Isozyme 1/Site 1 Protease

S1P is synthesized as an inactive precursor and undergoes multiple processing of its N-terminal prodomain involving the catalytic triad D218/H249/S414, generating S1P-A, S1P-B'/B, and S1P-C'/C.

“S1P is synthesized as an inactive precursor whose domain organization is shown in Fig. 4C. To become mature, S1P undergoes multiple processing of the N-terminal prodomain involving the catalytic triad D218/H249/S414, generating three shortened forms designated S1P-A, S1P-B’/B and S1P-C’/C (Espenshade et al., 1999; Elagoz et al., 2002; da Palma et al., 2014).”

S1P cleavage at the B'/B sites is required for subsequent cleavage at the C'/C sites.

“These results are consistent with the earlier work (Espenshade et al., 1999; da Palma et al., 2014), and suggest that S1P cleavage at the B’/B sites is required for subsequent cleavage at the C’/C sites.”

The prodomain of S1P is crucial for its folding, autoprocessing and proteolysis of substrates including SREBP2.

“Contrasting to those in other proprotein convertases that function as an inhibitor, the prodomain of S1P is crucial for its folding, autoprocessing and proteolysis of substrates including SREBP2 (da Palma et al., 2014; da Palma et al., 2016).”

Autoprocessing at the C'/C sites occurs in trans involving another S1P protein.

“autoprocessing at the C’/C sites is reported to occur in trans involving another S1P protein (Espenshade et al., 1999; da Palma et al., 2014)”

S1P-B'/B can already cleave the SREBP2 precursor and activate downstream signaling.

“Another unique aspect of S1P is that it needs not to be completely processed to become enzymatically active, as S1P-B’/B can already cleave the SREBP2 precursor and activate the downstream signaling (Espenshade et al., 1999; da Palma et al., 2014).”