Structural investigation of the C-terminal catalytic fragment of presenilin 1.
The gamma-secretase complex has a decisive role in the development of Alzheimer's disease, in that it cleaves a precursor to create the amyloid beta peptide whose aggregates form the senile plaques encountered in the brains of patients. Gamma-secretase is a member of the intramembrane-cleaving proteases which process their transmembrane substrates within the bilayer. Many of the mutations encountered in early onset familial Alzheimer's disease are linked to presenilin 1, the catalytic component of gamma-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin 1, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin 1, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.
Sobhanifar
Solmaz
S
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt/Main, Germany.
Schneider
Birgit
B
Löhr
Frank
F
Gottstein
Daniel
D
Ikeya
Teppei
T
Mlynarczyk
Krzysztof
K
Pulawski
Wojciech
W
Ghoshdastider
Umesh
U
Kolinski
Michal
M
Filipek
Slawomir
S
Güntert
Peter
P
Bernhard
Frank
F
Dötsch
Volker
V
D000595:Amino Acid Sequence; D055162:Biocatalysis; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry; D008823:Micelles; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D053764:Presenilin-1 / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D008051:Lipid Bilayers; D008823:Micelles; D053764:Presenilin-1
Nat Struct Biol. 2000 Feb;7(2):154-60
10655619
J Mol Biol. 2009 Jan 16;385(2):642-52
19013469
Protein Sci. 2006 Apr;15(4):684-98
16522799
J Comput Chem. 2007 Sep;28(12):2075-84
17405124
J Biol Chem. 1999 Aug 13;274(33):23647-58
10438548
Nature. 2008 Jan 31;451(7178):591-5
18235503
J Comput Chem. 2005 Dec;26(16):1701-18
16211538
J Biol Chem. 2006 Sep 15;281(37):27633-42
16844686
Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):1057-62
14732691
Nature. 2006 Nov 9;444(7116):179-80
17051161
Nat Protoc. 2007;2(11):2945-57
18007631
J Biol Chem. 1997 May 2;272(18):12047-51
9115271
J Biomol NMR. 2010 Jan;46(1):33-43
19680602
Science. 2005 Feb 25;307(5713):1317-21
15731457
Science. 2007 Dec 7;318(5856):1608-12
18063795
J Biol Chem. 2002 Aug 30;277(35):32046-53
12058030
J Am Chem Soc. 2006 Apr 5;128(13):4389-97
16569016
J Biol Chem. 2007 Nov 23;282(47):33985-93
17911105
J Biomol NMR. 2004 Jan;28(1):43-57
14739638
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6889-94
16636269
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7109-14
9618547
J Mol Graph. 1996 Feb;14(1):51-5, 29-32
8744573
J Mol Biol. 1982 May 5;157(1):105-32
7108955
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18999-9004
18024586
J Am Chem Soc. 2006 Mar 1;128(8):2697-704
16492056
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8262-7
18550820
Biochemistry. 2008 Apr 15;47(15):4552-64
18361503
Proteins. 2003 Aug 1;52(2):176-92
12833542
Mol Cell. 2008 Sep 26;31(6):896-908
18922471
EMBO J. 2004 Dec 8;23(24):4738-48
15549135
J Neurosci. 2008 Jun 11;28(24):6264-71
18550769
Biochemistry. 2005 Apr 5;44(13):5196-206
15794657
Cell. 2005 Feb 25;120(4):545-55
15734686
Biochim Biophys Acta. 1976 Oct 26;457(2):133-70
135582
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):14025-30
9391146
Biochemistry. 2000 May 9;39(18):5355-65
10820006
Methods Mol Biol. 2004;278:353-78
15318003
J Neurosci. 2006 Nov 15;26(46):12081-8
17108181
J Neurochem. 2006 Jan;96(1):218-27
16305624
Biochemistry. 2005 Sep 6;44(35):11821-8
16128583
Neuron. 1996 Nov;17(5):1015-21
8938132
J Biol Chem. 2005 Oct 21;280(42):35352-60
16046406
Biochemistry. 2004 May 25;43(20):6208-18
15147205
J Biol Chem. 2006 Sep 8;281(36):26569-77
16846981
J Mol Biol. 2001 Jan 19;305(3):567-80
11152613
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10836-40
8248178
Neurobiol Dis. 2009 Sep;35(3):352-8
19523517
Biophys J. 2003 Nov;85(5):3097-105
14581210
Biochemistry. 2007 Jun 12;46(23):6774-83
17511473
FEBS J. 2005 Jun;272(11):2727-33
15943807
Nature. 1999 Apr 8;398(6727):513-7
10206644
Science. 2009 Jun 26;324(5935):1726-9
19556511
Neuron. 1996 Nov;17(5):1023-30
8938133
Methods Mol Biol. 2007;375:57-78
17634596
Eur J Biochem. 1999 Apr;261(2):459-67
10215857
Protein Sci. 2008 Jul;17(7):1188-99
18434504
FEBS J. 2005 Dec;272(23):6024-38
16302967
J Phys Chem B. 2007 Jul 12;111(27):7812-24
17569554
J Biol Chem. 2008 Jul 11;283(28):19793-803
18482978
Neurobiol Dis. 2004 Apr;15(3):654-66
15056474