Opposing Effects of Glutamine and Asparagine Govern Prion Formation by Intrinsically Disordered Proteins

被引:144
作者
Halfmann, Randal [1 ,2 ]
Alberti, Simon [1 ]
Krishnan, Rajaraman [1 ]
Lyle, Nicholas [6 ]
O'Donnell, Charles W. [1 ,3 ,4 ]
King, Oliver D. [7 ]
Berger, Bonnie [3 ,5 ]
Pappu, Rohit V. [6 ]
Lindquist, Susan [1 ,2 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA
[3] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA
[4] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
[5] MIT, Dept Math, Cambridge, MA 02139 USA
[6] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA
[7] Boston Biomed Res Inst, Watertown, MA 02472 USA
关键词
YEAST PRION; SACCHAROMYCES-CEREVISIAE; RICH DOMAINS; COILED COILS; NEURODEGENERATIVE DISEASES; PSI PRION; AGGREGATION; POLYGLUTAMINE; SEQUENCE; SUP35;
D O I
10.1016/j.molcel.2011.05.013
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
Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein-folding diseases, bacterial biofilm assembly, and the inheritance of yeast prions (protein-based genetic elements). A systematic survey of prion-forming domains suggested that Q and N residues have distinct effects on amyloid formation. Here, we use cell biological, biochemical, and computational techniques to compare Q/N-rich protein variants, replacing Ns with Qs and Qs with Ns. We find that the two residues have strong and opposing effects: N richness promotes assembly of benign self-templating amyloids; Q richness promotes formation of toxic nonamyloid conformers. Molecular simulations focusing on intrinsic folding differences between Qs and Ns suggest that their different behaviors are due to the enhanced turn-forming propensity of Ns over Qs.
引用
收藏
页码:72 / 84
页数:13
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