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Prediction of intrinsically disordered proteins with a Low Computational Complexity Method

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Computer Modeling in Engineering & Sciences 2020年第10期125卷 111-123页

作者： Jia Yang Haiyuan Liu Hao He Nankai University School of Electronic Information and Optical EngineeringTianjin Key Laboratory of Optoelectronic Sensor and Sensing Network TechnologyTianjin300350China Hebei University of Technology Tianjin300400China

The prediction of intrinsically disordered proteins is a hot research area in *** to the high cost of experimental methods to evaluate disordered regions of protein sequences,it is becoming increasingly important to predict those regions through computational *** this paper,we developed a novel scheme by employing sequence complexity to calculate six features for each residue of a protein sequence,which includes the Shannon entropy,the topological entropy,the sample entropy and three amino acid preferences including Remark 465,Deleage/Roux,and Bfactor(2STD).Particularly,we introduced the sample entropy for calculating time series complexity by mapping the amino acid sequence to a time series of *** our knowledge,the sample entropy has not been previously used for predicting IDPs and hence is being used for the first time in our *** addition,the scheme used a properly sized sliding window in every protein sequence which greatly improved the prediction ***,we used seven machine learning algorithms and tested with 10-fold cross-validation to get the results on the dataset R80 collected by Yang et *** of the dataset DIS1556 from the Database of Protein Disorder(DisProt)(https://***)containing experimentally determined intrinsically disordered proteins(IDPs).The results showed that k-Nearest Neighbor was more appropriate and an overall prediction accuracy of 92%.Furthermore,our method just used six features and hence required lower computational complexity.

关键词： Bioinformatics intrinsically disordered proteins machine learning algorithms sequences computational complexity

Ligand discovery targeting intrinsically disordered proteins

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Ligand discovery targeting intrinsically disordered proteins

Phenotypic plasticity in prostate cancer： role of ntrinsically disordered proteins

2021年全国生物相分离和相变学术研讨会

作者：来鲁华 College of Chemistry and Molecular Engineering ＆ Center for Quantitative BiologyPeking University

intrinsically disordered proteins（IDPs） play central roles in many cellular processes,including transcription,translation,signal transduction,*** play key roles in biological condensate *** are strictly regulated and malfunction of the regulation process leads to various *** IDPs serve as potential therapeutic targets because of their prevalence in diseases,they are generally considered as undruggable due to the dynamic nature of their structures and the complexity of their binding with other *** currently known small molecules targeting IDPs were discovered by experimental *** structure based drug design methods cannot be directly applied in IDPs ligand *** group has been working on IDP drug design using combined computational and experimental *** this talk,I will introduce the approaches for IDP ligand design that we developed and demonstrate how we apply them in c-Myc and p53 ligand *** of compounds that bind to IDPs will be *** and opportunities for IDP drug design and biomolecular condensate regulation will be discussed.

关键词： intrinsically disordered proteins Drug design Biomolecular condensate regulation

来源： cnki会议评论

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Asian Journal of Andrology 2016年第5期18卷 704-710页

作者： Steven M Mooney Mohit Kumar Jolly Herbert Levine Prakash Kulkarni Department of Biology University of Waterloo Waterloo ON N2L 3G1 Canada Center for Theoretical Biological Physics Rice University Houston TX 77005 USA Department of Bioengineering Rice University Houston TX 77005 USA Department of Physics and Astronomy Rice University Houston TX 77005 USA institute for Bioscience and Biotechnology Research University of Maryland Rockville Maryland 20850 USA

A striking characteristic of cancer ceLls is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes such as a partial or complete epithelial to mesenchymal transition （EMT） that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks （PINs） may play a key role in determining phenotypic plasticity in prostate cancer （PCa）. Specifically, we point out that the key players driving transitions among different phenotypes （epithelial, mesenchymal, and hybrid epithelial/mesenchymal）, including ZEB1, SNAIl, OVOL1, and OVOL2, are intrinsically disordered proteins （IDPs） and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting iDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men.

关键词： epithelial to mesenchymal transition intrinsically disordered proteins prostate cancer state-switching

Transport receptor occupancy in nuclear pore complex mimics

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Nano Research 2022年第11期15卷 9689-9703页

作者： Alessio Fragasso Hendrik W.de Vries John Andersson Eli Ovan der Sluis Erik van der Giessen Patrick R.Onck Cees Dekker Department of Bionanoscience Kavli Institute of NanoscienceDelft University of TechnologyVan der Maasweg 9Delft 2629 HZThe Netherlands Zernike Institute for Advanced Materials University of GroningenNijenborgh 4Groningen 9747AGThe Netherlands Department of Chemistry and Chemical Engineering Chalmers University of TechnologyKemivägen 10Gothenburg SE-41296Sweden

Nuclear pore complexes(NPCs)regulate all molecular transport between the nucleus and the cytoplasm in eukaryotic *** disordered Phe-Gly nucleoporins(FG-Nups)line the central conduit of NPCs to impart a selective barrier where large proteins are excluded unless bound to a transport receptor(karyopherin;Kap).Here,we assess“Kap-centric”NPC models,which postulate that Kaps participate in establishing the selective *** combine biomimetic nanopores,formed by tethering Nsp1 to the inner wall of a solid-state nanopore,with coarse-grained modeling to show that yeast Kap95 exhibits two populations in Nsp1-coated pores:one population that is transported across the pore in milliseconds,and a second population that is stably assembled within the FG mesh of the *** current measurements show a conductance decrease for increasing Kap concentrations and noise data indicate an increase in rigidity of the *** reveals an accumulation of Kap95 near the pore wall,yielding a conductance *** find that Kaps only mildly affect the conformation of the Nsp1 mesh and that,even at high concentrations,Kaps only bind at most 8%of the FG-motifs in the nanopore,indicating that Kap95 occupancy is limited by steric constraints rather than by depletion of available *** data provide an alternative explanation of the origin of bimodal NPC binding of Kaps,where a stable population of Kaps binds avidly to the NPC periphery,while fast transport proceeds via a central FG-rich channel through lower affinity interactions between Kaps and the cohesive domains of Nsp1.

关键词： nuclear pore complex intrinsically disordered proteins nuclear transport receptors karyopherins nanopores biomimetics molecular dynamics coarse-grained modeling

MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth

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Journal of Molecular Cell Biology 2018年第3期10卷 195-204页

作者： Rachel Xi-Yeen Ho Rosana D. Meyer Kevin B. Chandler Esma Ersoy Michael Park Philip A. Bondzie Nima Rahimi Huihong Xu Catherine E. Costello Nader Rahimi Department of Pathology School of Medicine Boston University Medical Campus Boston MA 02118 USA Department of Biochemistry and Center for Biomedical Mass Spectrometry School of Medicine Boston University Medical Campus Boston MA 02118 USA

intrinsically disordered proteins （IDPs）/intrinsicaUy unstructured proteins are characterized by the lack of fixed or stable tertiary structure, and are increasingly recognized as an important class of proteins with major roles in signal transduction and transcriptional regulation. In this study, we report the identification and functional characterization of a previously uncharacterized protein （UPFO258/KIAA1024）, major intrinsically disordered Notch2-associated receptor 1 （MINAR1）. While MINAR1 carries a single transmembrane domain and a short cytoplasmic domain, it has a large extraceUular domain that shares no similarity with known protein sequences. Uncharacteristically, MINAR1 is a highly IDP with nearly 70% of its amino acids sequences unstructured. We demonstrate that MINAR1 physically interacts with Notch2 and its binding to Notch2 increases its stability and function. MINAR1 is widely expressed in various tissues including the epithelial cells of the breast and endothelial cells of blood vessels. MINAR1 plays a negative role in angioganesis as it inhibits angioganesis in cell culture and in mouse matrigal plug and zebraflsh anglo- genesis models. Furthermore, while MINAR1 is highly expressed in the normal human breast, its expression is significantly down- regulated in advanced human breast cancer and its re-expression in breast cancer cells inhibited tumor growth. Our study demonstrates that MINAR1 is an IDP that negatively regulates angioganesis and growth of breast cancer cells.

关键词： intrinsically disordered proteins Notch2 angiogenesis breast cancer MINAR1

Steroid hormone receptors and prostate cancer： role of structural dynamics in therapeutic targeting

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Asian Journal of Andrology 2016年第5期18卷 682-686页

作者： Raj Kumar Department of Basic Sciences The Commonwealth Medical College Scranton PA USA.

Steroid hormone receptors （SHRs） act in cell type- and gene-specific manner through interactions with coregulatory proteins to regulate numerous physiological and pathological processes at the level of gene regulation. Binding of steroid receptor modulator （SRM） ligand leads to allosteric changes in SHR to exert positive or negative effects on the expression of target genes. Due, in part, to the fact that current SRMs generally target ligand binding domain （LBD）/AF2 and neglect intrinsically disordered （ID） N-terminal domain （NTD）/AF1, clinically relevant SRMs lack selectivity and are also prone to the development of resistance over time. Therefore, to maximize the efficacy of SHR-based therapeutics, the possibility of developing unique modulators that act to control AF1 activity must be considered. Recent studies targeting androgen receptor＇s （AR＇s） ID AF1 domain for the castration-resistant prostate cancer has provided the possibility of therapeutically targeting ID NTD/AF1 surfaces by allosteric modulations to achieve desired effects. In this review article, we discuss how inter- and intra- molecular allosteric regulations controlled by AR＇s structural flexibility and dynamics particularly the ID NTD/AF1 is an emerging area of investigation, which could be exploited for drug development and therapeutic targeting of prostate cancer.

关键词： allosteric regulation coregulatory proteins endocrine cancers intrinsically disordered proteins steroid hormone receptors structural dynamics transactivation activity

Condensation of STM is critical for shoot meristem maintenance and salt tolerance in Arabidopsis

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Molecular Plant 2023年第9期16卷 1445-1459页

作者： Xiuwei Cao Qingwei Du Yahe Guo Ying Wang Yuling Jiao State Key Laboratory of Plant Genomics and National Center for Plant Gene Research(Beijing) Institute of Genetics and Developmental BiologyThe Innovative Academy of Seed DesignChinese Academy of SciencesBeijing 100101China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Beijing Agro-Biotechnology Research Center Beijing Academy of Agriculture and Forestry SciencesBeijing 100097China State Key Laboratory of Protein and Plant Gene Research School of Life SciencesPeking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences Center for Quantitative BiologyAcademy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China Peking University Institute of Advanced Agricultural Sciences Shandong Laboratory of Advanced Agricultural Sciences in WeifangWeifangShandong 261325China College of Advanced Agricultural Sciences University of Chinese Academy of SciencesBeijing 100049China

The shoot meristem generates the entire shoot system and is precisely maintained throughout the life cycle under various environmental *** this study,we identified a prion-like domain(PrD)in the key shoot meristem regulator SHOOT MERISTEMLESS(STM),which distinguishes STM from other related KNOX1 *** demonstrated that PrD stimulates STM to form nuclear condensates,which are required for maintaining the shoot *** nuclear condensate formation is stabilized by selected PrD-containing STM-interacting BELL proteins in vitro and in ***,condensation of STM promotes its interaction with the Mediator complex subunit MED8 and thereby enhances its transcriptional ***,condensate formation emerges as a novel regulatory mechanism of shoot meristem ***,we found that the formation of STM condensates is enhanced upon salt stress,which allows enhanced salt tolerance and increased shoot *** findings highlight that the transcription factor partitioning plays an important role in cell fate determination and might also act as a tunable environmental acclimation mechanism.

关键词： intrinsically disordered proteins KNOX1 shoot apical meristem biomolecular condensate salt stress axillary meristem

Mechanisms and regulation underlying membraneless organelle plasticity control

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Journal of Molecular Cell Biology 2021年第4期13卷 239-258页

作者： Hazrat Ismail Xu Liu Fengrui Yang Junying Li Ayesha Zahid Zhen Dou Xing Liu Xuebiao Yao MOE Key Laboratory for Membraneless Organelles&Cellular Dynamics and CAS Center for Excellence in Molecular Cell Science Hefei National Laboratory for Physical Sciences at the MicroscaleUniversity of Science and Technology of ChinaHefei 230027China Keck Center for Organoids Plasticity Control AtlantaGA 30310USA Anhui Key Laboratory for Cellular Dynamics&Chemical Biology Hefei 230027China

Evolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments,such as membrane-bound and membraneless organelles(MLOs),for spatiotemporal catalysis of physiochemical reactions essential for cell plasticity *** evidence and view support the notion that MLOs are built by multivalent interactions of biomolecules via phase separation and transition *** healthy cells,dynamic chemical modifications regulate MLO plasticity,and reversible phase separation is essential for cell *** evidence revealed that aberrant phase separation results in numerous neurodegenerative disorders,cancer,and other *** this review,we provide molecular underpinnings on(i)mechanistic understanding of phase separation,(ii)unifying structural and mechanistic principles that underlie this phenomenon,(iii)various mechanisms that are used by cells for the regulation of phase separation,and(iv)emerging therapeutic and other applications.

关键词： liquid-liquid phase separation membraneless organelles biomolecular condensates intrinsically disordered proteins post-translational modifications

Coexistence of α-helical and β-sheet structures in Membrane-bound human IAPP Indicates Two Distinct Aggregation Mechanisms

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Coexistence of α-helical and β-sheet structures in Membran...