Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein

Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent polymorphic fibrils upon spontaneous aggregation but become seed structure-dependent upon seeding.     

Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism

Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism.     

Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes

Chronic inflammation contributes to obesity mediated metabolic disturbances, including insulin resistance. Obesity is associated with altered microbial load in metabolic tissues that can contribute to metabolic inflammation. Different bacterial components such as, LPS, peptidoglycans have been shown to underpin metabolic disturbances through interaction with host innate immune receptors. Activation of Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) with specific peptidoglycan moieties promotes insulin resistance, inflammation and lipolysis in adipocytes. However, it was not clear how Nod1-mediated lipolysis and inflammation is linked. Here, we tested if Nod1-mediated lipolysis caused accumulation of lipid intermediates and promoted cell autonomous inflammation in adipocytes. We showed that Nod1-mediated lipolysis caused accumulation of diacylglycerol (DAG) and activation of PKCδ in 3T3-L1 adipocytes, which was prevented with a Nod1 inhibitor. Nod1-activated PKCδ caused downstream stimulation of IRAK1/4 and was associated with increased expression of proinflammatory cytokines such as, IL-1β, IL-18, IL-6, TNFα and MCP-1. Pharmacological inhibition or siRNA mediated knockdown of IRAK1/4 attenuated Nod1-mediated activation of NF-κB, JNK, and the expression of proinflammatory cytokines. These results reveal that Nod1-mediated lipolysis promoted accumulation of DAG, which engaged PKCδ and IRAK1/4 to augment inflammation in 3T3-L1 adipocytes.     

基因外显子连接序列与相应内含子序列的相互作用

剪接后的内含子与相应mRNA序列的相互作用在基因表达调控过程中起着非常重要的作用。基于27个物种的核糖核蛋白基因序列,采用Smith—Waterman局域比对方法得到外显子连接序列与相应内含子序列的最佳匹配片段,分析了外显子连接序列上的匹配频率分布和匹配片段的序列特征。发现一些低等真核生物EJC结合区域的匹配频率明显低于其它区域,所有物种EJC结合区域的序列构成呈现出相对低的结构序。最佳匹配片段的平均长度和配对率分布与siRNA和miRNA的结合特征相同。推测EJC和内含子在与外显子序列结合的过程中存在相互竞争和相互协作的关系,内含子中部序列在基因表达调控过程中起着重要的作用。     

基于压缩氨基酸和支持向量机进行膜蛋白类型识别

膜蛋白是一类结构独特的蛋白质,是细胞执行各种功能的物质基础。根据其在细胞膜上的不同存在方式,主要分为六种类型。本文利用压缩的氨基酸对原始膜蛋白序列进行信息压缩,再对压缩序列进行氨基酸组成和顺序特征的提取,最后采用支持向量机构建分类模型。通过五叠交叉验证的结果表明,该方法对于六种膜蛋白的分类预测,准确度最高可达98％以上,平均预测准确度在85％以上,可有效实现膜蛋白六种类型的划分,为进一步分析膜蛋白的结构和功能奠定基础。     

基于CNN与LSTM模型的蛋白质二级结构预测

蛋白质结构的预测在理解蛋白质结构组成和蛋白质的生物学功能有重要意义,而蛋白质二级结构预测是蛋白质结构预测的重要环节。当PSSM位置特异性进化矩阵被广泛应用于将蛋白质初级结构序列编码作为输入样本后,每个残基可以被表示成二维空间的数据平面,由此文中尝试利用卷积神经网络对其进行训练。文中还设计了另一种卷积神经网络,利用长短记忆网络感知了CNN最后卷积特征面的横向特征和纵向特征后连同卷积神经网络的全连接共同完成分类,最后用ensemble方法对两类卷积神经网络模型进行了整合,最终ensemble方法中包含两类卷积神经网络的六个模型,在CB513蛋白质数据集测得的Q3结果为77.2。     

降糖肽的发展现状及研究进展

糖尿病是一组以高血糖为特征的代谢性疾病,是由于胰岛素分泌缺陷或其生物功能受损,或两者兼有引起。糖尿病可能导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。糖尿病主要分为Ⅰ型糖尿病和Ⅱ型糖尿病,这两类糖尿病均存在明显的遗传异质性。目前用于降低或控制血糖的药物主要有硫脉类、双肌类、苯甲酸衍生物类、糖苷酶抑制剂类和噻唑烷二酮类。研发出安全有效的降糖药物已经成为全世界关注的焦点,其中,生物活性肽是目前最广泛研究的潜在治疗剂之一,其最佳用途正在开发中。迄今为止,已经发现了许多天然肽和合成肽,其具有通过不同机制介导的优异的抗糖尿病效果。新兴技术和药物输送系统的应用进一步促进了预期目标成果的达成。临床前和临床研究中一些具有更好效力和安全性的优秀肽已经被确定。因此,对这些肽的进一步详细研究可能会筛选出临床上有用的抗糖尿病药物。     

新型冠状病毒(SARS-CoV-2)蛋白靶位的生信分析

目前新型冠状病毒肺炎(COVID-19)疫情仍在全球肆虐,但尚无针对该病毒的治疗特效药.在此背景,以美国化学文摘社(Chemical Abstracts Service,CAS)提供的SARS-CoV-2病毒及宿主蛋白靶标为研究对象,运用基因功能富集、蛋白网络等方法进行生物信息分析.结果发现,人网格蛋白介导型内吞和依赖...     

基于设计模板的BRD-like折叠类型综合分类方法

蛋白质折叠规律研究是生命科学重大前沿课题,折叠类型分类是蛋白质折叠研究的基础。构建BRD-like折叠类型模板数据库,建立了基于多模板的综合分类方法,并用于该折叠类型的分类。对实验集的12 117个样本进行检验,结果的敏感性、特异性分别为0.923和0.997,MCC值为0.72;对独立检验集2 260个样本的检验,结果发现:敏感性、特异性分别为0.941和0.998,MCC值为0.86.结果表明:基于多模板的综合分类方法可用于蛋白质折叠类型分类。