The
            <i>Caenorhabditis elegans</i>
            IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

Grigorenko, Anastasia P.; Moliaka, Yuri K.; Soto, Martha C.; Mello, Craig C.; Rogaev, Evgeny I.

doi:10.1073/pnas.0406462101

Cited by 54 publications

(54 citation statements)

References 48 publications

(54 reference statements)

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“…Deficiency of the Caenorhabditis elegans imp-2 gene, which corresponds to vertebrate SPP, also caused a severe developmental phenotype, which could be mimicked by reduced cholesterol concentrations or the disruption of Ce-Irp-1 (48 with lipoprotein receptor-related proteins appears to result in neurodegeneration in mice (49), a phenotype also observed upon down-regulation of spp in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Differential Localization and Identification of a Critical Aspartate Suggest Non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3

Krawitz¹,

Haffner²,

Fluhrer³

et al. 2005

Journal of Biological Chemistry

114

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Signal peptide peptidase (SPP) is an unusual aspartyl protease that mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the ␥-secretase complex, SPP contains a critical GXGD motif in its C-terminal catalytic center. Although SPP is known to be an aspartyl protease of the GXGD type, several presenilin homologues/SPP-like proteins (PSHs/SPPL) of unknown function have been identified by data base searches. We now investigated the subcellular localization and a putative proteolytic activity of PSHs/SPPLs in cultured cells and in an in vivo model. We demonstrate that SPPL2b is targeted through the secretory pathway to endosomes/lysosomes, whereas SPP and SPPL3 are restricted to the ER. As suggested by the differential subcellular localization of SPPL2b compared with SPP and SPPL3, we found distinct phenotypes upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutations of the putative C-terminal active sites of spp, sppl2, and sppl3 produced phenocopies of the respective knockdown phenotypes. Thus, our data suggest that all investigated PSHs/SPPLs are members of the novel family of GXGD aspartyl proteases. Furthermore, SPPL2b is shown to be the first member of the SPP/PSH/SPPL family that is not located within the ER but in endosomal/lysosomal vesicles.

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Section: Discussionmentioning

confidence: 99%

Differential Localization and Identification of a Critical Aspartate Suggest Non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3

Krawitz¹,

Haffner²,

Fluhrer³

et al. 2005

Journal of Biological Chemistry

114

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“…In the presence of EDTA, membrane-bound ribosomes are separated from the rough ER. Under these conditions, AtSPP shifted to lower-density fractions (fractions [12][13][14][15][16][17][18][19], along with BiP (fractions 8-19) (Fig. 6B).…”

Section: Endogenous Atspp In 'Deep' Cells Localizes To the Er Membranementioning

confidence: 99%

“…SPP orthologs have been identified in humans [10], mice [15], zebrafish [16], Drosophila [17] and Caneorhabditis elegans [18]. Human SPP (HsSPP) has been implicated in immunological responses by cleavage of MHC class I signal peptide [19], maturation of proteins of hepatitis C virus [20], hepatitis G virus [21], and pestiviruses [22] by cleavage of their core proteins, and acceleration of prolactin secretion by cleavage of its signal peptide [23].…”

mentioning

confidence: 99%

Signal peptide peptidase and its homologs in Arabidopsis thaliana– plant tissue‐specific expression and distinct subcellular localization

et al. 2007

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Signal peptide peptidase (SPP) is an aspartic proteinase that hydrolyses its substrate within the plane of the cellular membrane. In vertebrates, it plays crucial roles in life processes such as differentiation, embryogenesis, cell signaling and immunological response. We first found SPP in plants. An ortholog of human SPP (AtSPP), and its five AtSPP homologs (AtSPPL1-AtSPPL5), were searched for in the Arabidopsis database. These clones were grouped into three different clusters: AtSPP was grouped with human SPP (HsSPP) orthologs, AtSPPL1 with the HsSPPL3 family, and AtSPPL2-AtSPPL5 with the group of SPP-like proteins of plant origin. AtSPP, AtSPPL1 and AtSPPL2 were examined for their expression profiles by in situ hybridization. AtSPP was strongly expressed in both the shoot meristem of germinating seeds and the inflorescence meristem at the reproductive stage. On the other hand, AtSPPL1 and AtSPPL2 were expressed in the shoot meristem of germinating seeds, but at very low levels in the shoot apex at the reproductive stage. The subcellular localization of AtSPP, AtSPPL1 and AtSPPL2 was investigated using green fluorescent protein (GFP) fusion proteins in cultured 'Deep' cells. GFP-AtSPP localized to the endoplasmic reticulum (ER), and GFP-AtSPPL1 and GFP-AtSPPL2 to the endosomes. These results suggest that AtSPP mediates the cleavage of signal peptide in the ER membrane as well as HsSPP does, and also that AtSPPL1 and AtSPPL2 located in the endosomes have distinct roles in cells.Abbreviations 2SC, pumpkin 2S albumin; AP, aspartic proteinase; At, Arabidopsis thaliana; BiP, luminal binding protein; ER, endoplasmic reticulum; GFP, green fluorescent protein; Hs, Homo sapiens; I-CliP, intramembrane-cleaving protease; PIP1, plasma membrane intrinsic protein 1; SPP, signal peptide peptidase; SPPL, signal peptide peptidase-like protein; V-PPase, vacuolar-type proton pyrophosphatase.

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“…Moreover, some endoproteolytic products generated by SPP cleavage directly mediate signal transduction (15,16). In fact, loss-of-function studies of SPP in model animals resulted in severe developmental defects, inferring a vital role of SPP in metazoan development (17)(18)(19). Furthermore, a growing body of evidence indicates that SPP activity plays an important role in the maturation of several pathogens including the hepatitis C virus and the malaria parasite (7,20).…”

mentioning

confidence: 99%

Three-dimensional Structure of the Signal Peptide Peptidase

Miyashita

Maruyama

Isshiki

et al. 2011

Journal of Biological Chemistry

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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.The intramembrane-cleaving proteases (I-CLiPs) 5 that sever the transmembrane domains of their substrates have been identified in a range of organisms and play a variety of roles in

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The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins

Cited by 54 publications

References 48 publications

Differential Localization and Identification of a Critical Aspartate Suggest Non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3

Differential Localization and Identification of a Critical Aspartate Suggest Non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3

Signal peptide peptidase and its homologs in Arabidopsis thaliana– plant tissue‐specific expression and distinct subcellular localization

Three-dimensional Structure of the Signal Peptide Peptidase

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