title: Three-dimensional structure of the signal peptide peptidase.
abstract: Signal peptide peptidase (SPP) is an atypical aspartic protease that hydrolyzes peptide bonds within the transmembrane domain of substrates and is implicated in several biological and pathological functions. Here, we analyzed the structure of human SPP by electron microscopy and reconstructed the three-dimensional structure at a resolution of 22 Å. Enzymatically active SPP forms a slender, bullet-shaped homotetramer with dimensions of 85 × 85 × 130 Å. The SPP complex has four concaves on the rhombus-like sides, connected to a large chamber inside the molecule. Intriguingly, the N-terminal region of SPP is sufficient for the tetrameric assembly. Moreover, overexpression of the N-terminal region inhibited the formation of the endogenous SPP tetramer and the proteolytic activity within cells. These data suggest that the homotetramer is the functional unit of SPP and that its N-terminal region, which works as the structural scaffold, has a novel modulatory function for the intramembrane-cleaving activity of SPP.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Yuusuke
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Hayato
authors.initials: H
authors.lastname: Isshiki
authors.forename: Satoko
authors.initials: S
authors.lastname: Osawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ogura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mio
authors.forename: Chikara
authors.initials: C
authors.lastname: Sato
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase