title: An internal signal sequence directs intramembrane proteolysis of a cellular immunoglobulin domain protein.
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.
authors.affiliation: Department of Physiology & Cellular Biophysics, Columbia University, New York, New York 10032, USA.
authors.forename: Thalia
authors.initials: T
authors.lastname: Robakis
authors.forename: Beata
authors.initials: B
authors.lastname: Bak
authors.forename: Shu-huei
authors.initials: SH
authors.lastname: Lin
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
authors.forename: Peter
authors.initials: P
authors.lastname: Scheiffele
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry* / Q000502:physiology*; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D021382:Protein Sorting Signals