Elimination of the Native Structure and Solubility of the hVAPB MSP Domain by the Pro56Ser Mutation That Causes Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化 突变 领域(数学分析) 溶解度 化学 遗传学 医学 生物 生物化学 内科学 数学 有机化学 疾病 基因 数学分析
作者
Jiahai Shi,Shixiong Lua,Justina Shihui Tong,Jianxing Song
出处
期刊:Biochemistry [American Chemical Society]
卷期号:49 (18): 3887-3897 被引量:46
标识
DOI:10.1021/bi902057a
摘要

The Pro56Ser mutation in the human VAPB MSP domain causes a familial amyotrophic lateral sclerosis. Here we present the first structural investigation of both wild-type and Pro56Ser mutant MSP domains. The results reveal that the wild-type MSP domain is well-folded at neutral pH but can undergo acid-induced unfolding reversibly. It has a thermodynamic stability energy (ΔG°N−U) of 7.40 kcal/mol and is also active in binding to a Nir2 peptide with a KD of 0.65 μM. Further determination of its crystal structure reveals that it adopts a seven-strand immunoglobulin-like β sandwich in which Pro56 adopts the unusual cis-peptide bond conformation that appears to be critical in maintaining the characteristic S-shaped loop. Markedly, the Pro56Ser mutation renders the MSP domain insoluble in buffer. Nevertheless, as facilitated by our recent discovery that "insoluble proteins" can be solubilized in salt-free water, we have successfully characterized the residue-specific conformation of the Pro56Ser mutant by CD and heteronuclear NMR spectroscopy. The Pro56Ser mutant remains lacking of the native tight packing and secondary structures under various conditions and was further characterized as having a non-native helical conformation weakly populated at pH 3.5. Intriguingly, Pro12 located in another S-shaped loop also adopts the cis-peptide bond conformation, and its mutation to Ser is able to make the MSP domain highly insoluble and unfolded like the Pro56Ser mutant. Our study thus implies that the Pro56Ser mutation might lead to ALS by eliminating the native MSP structure, which consequently leads to aggregation and loss of functions under physiological conditions.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
jinshan关注了科研通微信公众号
2秒前
3秒前
3秒前
orixero应助ycc采纳,获得40
3秒前
4秒前
蔡小葵完成签到 ,获得积分10
4秒前
5秒前
馒头完成签到,获得积分10
6秒前
7秒前
7秒前
龙傲天完成签到,获得积分10
7秒前
ptsoup发布了新的文献求助10
7秒前
happy发布了新的文献求助10
8秒前
8秒前
Yziii应助老虎采纳,获得10
8秒前
忧郁平文发布了新的文献求助10
9秒前
科研通AI2S应助小杨采纳,获得10
9秒前
田様应助李西瓜采纳,获得10
9秒前
10秒前
LY发布了新的文献求助60
10秒前
左登峰发布了新的文献求助10
11秒前
zhaoman完成签到,获得积分10
11秒前
筱12完成签到,获得积分10
11秒前
葛儿完成签到 ,获得积分10
11秒前
13秒前
14秒前
科目三应助happy采纳,获得10
14秒前
难过冷玉完成签到,获得积分10
14秒前
zjh完成签到,获得积分10
14秒前
manchang完成签到 ,获得积分10
15秒前
xsc发布了新的文献求助10
17秒前
17秒前
奇奇淼发布了新的文献求助10
19秒前
白干发布了新的文献求助10
19秒前
21秒前
21秒前
语上发布了新的文献求助30
22秒前
oboul完成签到,获得积分10
22秒前
彭于晏应助娃哈哈采纳,获得10
24秒前
24秒前
高分求助中
The late Devonian Standard Conodont Zonation 2000
Nickel superalloy market size, share, growth, trends, and forecast 2023-2030 2000
The Lali Section: An Excellent Reference Section for Upper - Devonian in South China 1500
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Very-high-order BVD Schemes Using β-variable THINC Method 830
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 800
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 800
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3248024
求助须知:如何正确求助?哪些是违规求助? 2891212
关于积分的说明 8266791
捐赠科研通 2559415
什么是DOI,文献DOI怎么找? 1388257
科研通“疑难数据库(出版商)”最低求助积分说明 650711
邀请新用户注册赠送积分活动 627641