Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): Does APP function as a cholesterol sensor?

被引:146
作者
Beel, Andrew J. [1 ,2 ]
Mobley, Charles K. [1 ,2 ]
Kim, Hak Jun [1 ,2 ]
Tian, Fang [3 ]
Hadziselimovic, Arina [1 ,2 ]
Jap, Bing [4 ]
Prestegard, James H. [3 ]
Sanders, Charles R. [1 ,2 ]
机构
[1] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN 37232 USA
[3] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA
[4] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA
关键词
D O I
10.1021/bi800993c
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The amyloid precursor protein (APP) is subject I to alternative pathways of proteolytic processing, leading either to production of the amyloid-beta (A beta) peptides or to non-amyloidogenic fragments. Here, we report the first structural study of C99, the 99-residue transmembrane C-terminal domain of APP liberated by beta-secretase cleavage. We also show that cholesterol, an agent that promotes the amyloidogenic pathway, specifically binds to this protein. C99 was purified into model membranes where it was observed to homodimerize. NMR data show that the transmembrane domain of C99 is an (x-helix that is flanked on both sides by mostly disordered extramembrane domains, with two exceptions. First, there is a short extracellular surface-associated helix located just after the site of alpha-secretase cleavage that helps to organize the connecting loop to the transmembrane domain, which is known to be essential for A production. Second, there is a surface-associated helix located at the cytosolic C-terminus, adjacent to the YENPTY motif that plays critical roles in APP trafficking and protein-protein interactions. Cholesterol was seen to participate in saturable interactions with C99 that are centered at the critical loop connecting the extracellular helix to the transmembrane domain. Binding of cholesterol to C99 and, most likely, to APP may be critical for the trafficking of these proteins to cholesterol-rich membrane domains, which leads to cleavage by beta- and gamma-secretase and resulting amyloid-beta production. It is proposed that APP may serve as a cellular cholesterol sensor that is linked to mechanisms for suppressing cellular cholesterol uptake.
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收藏
页码:9428 / 9446
页数:19
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