Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction

被引：167

作者：

Anastasia, Agustin ^{[1
]}

Deinhardt, Katrin ^{[2
,3
,4
]}

Chao, Moses V. ^{[2
]}

Will, Nathan E. ^{[1
]}

Irmady, Krithi ^{[1
]}

Lee, Francis S. ^{[5
]}

Hempstead, Barbara L. ^{[1
]}

Bracken, Clay ^{[6
]}

机构：

[1] Cornell Univ, Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[2] NYU, Sch Med, Skirball Inst, New York, NY 10016 USA

[3] Univ Southampton, Ctr Biol Sci, Southampton SO17 1BJ, Hants, England

[4] Univ Southampton, Inst Life Sci, Southampton SO17 1BJ, Hants, England

[5] Cornell Univ, Weill Cornell Med Coll, Dept Psychiat, New York, NY 10065 USA

[6] Cornell Univ, Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

关键词：

INTRINSICALLY DISORDERED PROTEINS; ACTIVITY-DEPENDENT SECRETION; NEUROTROPHIC FACTOR; ALPHA-SYNUCLEIN; WILD-TYPE; SORTILIN; PROBDNF; HIPPOCAMPUS; TRAFFICKING; ACTIVATION;

D O I：

10.1038/ncomms3490

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：

A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.

引用

页数：12

共 48 条

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