Plasma membrane localization signals in the light chain of botulinum neurotoxin

被引：87

作者：

Fernández-Salas, E ^{[1
]}

Steward, LE ^{[1
]}

Ho, H ^{[1
]}

Garay, PE ^{[1
]}

Sun, SW ^{[1
]}

Gilmore, MA ^{[1
]}

Ordas, JV ^{[1
]}

Wang, J ^{[1
]}

Francis, J ^{[1
]}

Aoki, KR ^{[1
]}

机构：

[1] Allergan Pharmaceut Inc, Dept Biol Sci, Neurotoxin Res Program, Irvine, CA 92612 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2004年 / 101卷 / 09期

关键词：

SNARE; subcellular localization; dileucine motif; duration of action; Clostridium;

D O I：

10.1073/pnas.0400229101

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Botulinum neurotoxin (BoNT) is a potent biological substance used to treat neuromuscular and pain disorders. Both BoNT type A and BoNT type E display high-affinity uptake into motor neurons and inhibit exocytosis through cleavage of the synaptosome-associated protein of 25 kDa (SNAP25). The therapeutic effects of BoNT/A last from 3 to 12 months, whereas the effects of BoNT/E last less than 4 weeks. Using confocal microscopy and site-specific mutagenesis, we have determined that the protease domain of BoNT/A light chain (BoNT/ A-LC) localizes in a punctate manner to the plasma membrane, colocalizing with the cleaved product, SNAP25(197). In contrast, the short-duration BoNT/E serotype is cytoplasmic. Mutations in the BoNT/A-LC have revealed sequences at the N terminus necessary for plasma membrane localization, and an active dileucine motif in the C terminus that is likely involved in trafficking and interaction with adaptor proteins. These data support sequence-specific signals as determinants of intracellular localization and as a basis for the different durations of action in these two BoNT serotypes.

引用

页码：3208 / 3213

页数：6

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