Conserved stress-protective activity between prion protein and Shadoo.
Shadoo (Sho) is a neuronally expressed glycoprotein of unknown function. Although there is no overall sequence homology to the cellular prion protein (PrP(C)), both proteins contain a highly conserved internal hydrophobic domain (HD) and are tethered to the outer leaflet of the plasma membrane via a C-terminal glycosylphosphatidylinositol anchor. A previous study revealed that Sho can reduce toxicity of a PrP mutant devoid of the HD (PrPΔHD). We have now studied the stress-protective activity of Sho in detail and identified domains involved in this activity. Like PrP(C), Sho protects cells against physiological stressors such as the excitotoxin glutamate. Moreover, both PrP(C) and Sho required the N-terminal domain for this activity; the stress-protective capacity of PrPΔN as well as ShoΔN was significantly impaired. In both proteins, the HD promoted homodimer formation; however, deletion of the HD had different effects. Although ShoΔHD lost its stress-protective activity, PrPΔHD acquired a neurotoxic potential. Finally, we could show that the N-terminal domain of PrP(C) could be functionally replaced by that of Sho, suggesting a similar function of the N termini of Sho and PrP(C). Our study reveals a conserved physiological activity between PrP(C) and Sho to protect cells from stress-induced toxicity and suggests that Sho and PrP(C) might act on similar signaling pathways.
Neurobiochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, D-80336 Munich, Germany.
Vignesh
V
Sakthivelu
Ralf P
RP
Seidel
Konstanze F
KF
Winklhofer
Jörg
J
Tatzelt
D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013312:Stress, Physiological
D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D018621:PrPC Proteins; C478971:SPRN protein, human
EMBO J. 2008 Jul 23;27(14):1974-84
18566584
Nature. 1996 Jan 25;379(6563):339-43
8552188
Science. 2005 Jun 3;308(5727):1435-9
15933194
Nature. 1996 Jul 11;382(6587):180-2
8700211
EMBO J. 2007 Jan 24;26(2):538-47
17245436
Cold Spring Harb Symp Quant Biol. 1996;61:511-22
9246477
Biochem Biophys Res Commun. 2006 Mar 3;341(1):218-24
16414019
EMBO J. 1996 Mar 15;15(6):1255-64
8635458
Cell. 1993 Jul 2;73(7):1339-47
8100741
Brain Pathol. 2007 Apr;17(2):174-83
17388948
FEBS Lett. 1997 Aug 18;413(2):282-8
9280298
Biochim Biophys Acta. 2007 Jun;1772(6):629-44
17451912
J Biol Chem. 2003 Apr 25;278(17):14961-70
12556465
Mol Biol Cell. 2006 Aug;17(8):3356-68
16707568
Science. 2003 Oct 31;302(5646):871-4
14593181
J Virol. 1987 Dec;61(12):3688-93
2446004
Biotechniques. 2008 Sep;45(3):340-3
18778261
Br Med Bull. 2003;66:1-20
14522845
J Biol Chem. 2005 Mar 11;280(10):9320-9
15591591
EMBO J. 2007 Jan 24;26(2):548-58
17245437
Biol Chem. 2000 May-Jun;381(5-6):463-9
10937879
Annu Rev Neurosci. 2001;24:519-50
11283320
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13452-7
9391046
Cell. 1998 May 1;93(3):337-48
9590169
Bioessays. 2009 Mar;31(3):328-35
19260013
Amyloid. 2004 Sep;11(3):162-72
15523918
EMBO J. 2008 Jan 23;27(2):336-49
18216876
EMBO J. 2007 Sep 5;26(17):4038-50
17703189
Gene. 2003 Sep 18;314:89-102
14527721
Cell. 1998 Apr 17;93(2):203-14
9568713