Abstract
Precursor proteolysis is a crucial mechanism for regulating protein structure and function. Signal peptidase (SP) is an enzyme with a well defined role in cleaving N-terminal signal sequences but no demonstrated function in the proteolysis of cellular precursor proteins. We provide evidence that SP mediates intraprotein cleavage of IgSF1, a large cellular Ig domain protein that is processed into two separate Ig domain proteins. In addition, our results suggest the involvement of signal peptide peptidase (SPP), an intramembrane protease, which acts on substrates that have been previously cleaved by SP. We show that IgSF1 is processed through sequential proteolysis by SP and SPP. Cleavage is directed by an internal signal sequence and generates two separate Ig domain proteins from a polytopic precursor. Our findings suggest that SP and SPP function are not restricted to N-terminal signal sequence cleavage but also contribute to the processing of cellular transmembrane proteins.
Highlights
Proteolysis is one of the central mechanisms regulating tissue morphogenesis and cellular functions
IgSF1 Contains an Internal Signal Sequence—Based on the apparent molecular masses of the N- and C-terminal fragments, as well as the location of the epitope localized by the C-terminal domain (CTD) antibody, we predicted that the cleavage site should be the protein in the endoplasmic reticulum (ER), only the CTD antibody detected protein located within amino acids 400 –560 of full-length IgSF1
Whereas the first hydrophobic domain of IgSF1 could be replaced by the stop transfer sequence of CD47 without affecting processing (CD47/ IgSF1), cleavage was abolished in chimeras that contained only CD47 transmembrane domains (CD47) or that lacked the c-region of the internal IgSF1 signal peptide (IgSF1⌬c)
Summary
Proteolysis is one of the central mechanisms regulating tissue morphogenesis and cellular functions. Our findings suggest that SP and SPP function are not restricted to N-terminal signal sequence cleavage and contribute to the processing of cellular transmembrane proteins.
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