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For over a decade, mechanistic studies of protein translocation into the mammalian ER have relied on proteoliposomes with translocons reconstituted from purified components, a system that efficiently translocates simple model proteins like prolactin, but often fails to match in vivo translocation efficiency for other substrates. On page 529, Fons et al. explain why by showing that the TRAP complex, previously considered dispensable for translocation, is actually a substrate-specific functional component of the mammalian translocon. The work suggests that accessory complexes like TRAP could help to drive both normal and pathological cell physiology.2 _. W8 ]( V. V8 c4 F+ Q, B! I
. E& q6 Z# h1 Z! n0 c+ ?In the standard reconstituted system, prion protein (PrP) either fails to translocate or becomes stuck as a transmembrane protein, problems that are also observed in some neurodegenerative prion diseases. The authors exploited this defect to purify a factor that stimulates complete translocation of PrP, and identified the factor as TRAP. TRAP also stimulates the translocation of several other proteins. The TRAP dependence of a protein is determined primarily by its signal sequence: the less efficient a signal sequence is at initiating substrate translocation, the more it requires TRAP.$ J6 j/ G4 c2 o7 |' W R) x
% v* E; d U* U' sThus, the core machinery of translocation may be assisted by accessory factors for different classes of substrates. As signal sequences are highly divergent among substrates, factors like TRAP might be regulated to control specific physiological events within the cell. The apparent defects in PrP translocation in certain prion diseases raises the intriguing possibility that changes in the expression or activity of TRAP could also contribute to pathogenesis.
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, u/ m( T a6 m0 |( sThe authors are now extending their analysis of translocons with and without TRAP. They hope to determine whether TRAP acts directly by binding to the translocating substrate, or indirectly by altering the structure of the translocon.(Different signal sequences rely on TRAP ) |
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发表于 2009-3-6 00:46
发表于 2015-6-10 18:42
