scholarly journals Short loop motif profiling of protein interaction networks in acute myeloid leukaemia

2018 ◽  
Author(s):  
Sun Sook Chung ◽  
Anna Laddach ◽  
N. Shaun B. Thomas ◽  
Franca Fraternali
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Protein Interactions ◽  
Active Sites ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Ppi Networks ◽  
Short Loop ◽  
Genomics And Proteomics ◽  
Acute Myeloid

AbstractRecent advances in biotechnologies for genomics and proteomics have expanded our understanding of biological components which play crucial roles in complex mechanisms related to cancer. However, it is still challenging to extract from the available knowledge reliable targets to use in a translational setting. The reasons for this are manifold, but essentially distilling real biological signal from heterogeneous “big data” collections is the major hurdle. Here, we aim to establish an in-silico pipeline to explore mutations and their effects on protein-protein interactions, with a focus on acute myeloid leukaemia (AML), one of the most common blood cancers with the highest mortality rate. Our method, based on cyclic interactions of a small number of proteins topologically linked in the network (short loop network motifs), highlights specific protein-protein interactions (PPIs) and their functions in AML when compared with other leukaemias. We also developed a new property named ‘short loop commonality’ to measure indirect PPIs occurring via common short loop interactions. This new method detects “modules” of PPI networks (PPINs) enriched with common biological functions which have proteins that contain mutation hotspots. We further perform 3D structural modelling to extract atomistic details, which shows that such hotspots map to PPI interfaces as well as active sites. Thus, our study proposes a framework for the macroscopic and microscopic investigation of PPINs, their relation to cancers, and highlights important functional modules in the network to be exploited in targeted drug screening.

scholarly journals Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Sun Sook Chung ◽  
Joseph C F Ng ◽  
Anna Laddach ◽  
N Shaun B Thomas ◽  
Franca Fraternali
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Interaction Network ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Short Loop ◽  
New Strategy ◽  
Loop Network ◽  
Protein Protein Interaction Network

Abstract Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein–protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein–Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named ‘short loop commonality’ to measure indirect PPIs occurring via common SLM interactions. This detects ‘modules’ of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR–Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

New advances in extracting and learning from protein–protein interactions within unstructured biomedical text data

2019 ◽  
Vol 3 (4) ◽  
pp. 357-369
Author(s):  
J. Harry Caufield ◽  
Peipei Ping
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Historical Context ◽  
Specific Protein ◽  
Basic Unit ◽  
Biomedical Text ◽  
Protein Protein Interactions ◽  
Text Data ◽  
Ppi Networks ◽  
Protein Functions

Abstract Protein–protein interactions, or PPIs, constitute a basic unit of our understanding of protein function. Though substantial effort has been made to organize PPI knowledge into structured databases, maintenance of these resources requires careful manual curation. Even then, many PPIs remain uncurated within unstructured text data. Extracting PPIs from experimental research supports assembly of PPI networks and highlights relationships crucial to elucidating protein functions. Isolating specific protein–protein relationships from numerous documents is technically demanding by both manual and automated means. Recent advances in the design of these methods have leveraged emerging computational developments and have demonstrated impressive results on test datasets. In this review, we discuss recent developments in PPI extraction from unstructured biomedical text. We explore the historical context of these developments, recent strategies for integrating and comparing PPI data, and their application to advancing the understanding of protein function. Finally, we describe the challenges facing the application of PPI mining to the text concerning protein families, using the multifunctional 14-3-3 protein family as an example.

scholarly journals Picornaviral polymerase domain exchanges reveal a modular basis for distinct biochemical activities of viral RNA-dependent RNA polymerases

2020 ◽  
Vol 295 (31) ◽  
pp. 10624-10637 ◽  
Author(s):  
Colleen L. Watkins ◽  
Brian J. Kempf ◽  
Stéphanie Beaucourt ◽  
David J. Barton ◽  
Olve B. Peersen
Keyword(s):  
Protein Interactions ◽  
Active Sites ◽  
Specific Protein ◽  
Rna Polymerases ◽  
Viral Fitness ◽  
Structural Basis ◽  
Protein Protein Interactions ◽  
Elongation Complex ◽  
Domain Interactions ◽  
Species Specific

Picornaviral RNA-dependent RNA polymerases (RdRPs) have low replication fidelity that is essential for viral fitness and evolution. Their global fold consists of the classical “cupped right hand” structure with palm, fingers, and thumb domains, and these RdRPs also possess a unique contact between the fingers and thumb domains. This interaction restricts movements of the fingers, and RdRPs use a subtle conformational change within the palm domain to close their active sites for catalysis. We have previously shown that this core RdRP structure and mechanism provide a platform for polymerases to fine-tune replication rates and fidelity to optimize virus fitness. Here, we further elucidated the structural basis for differences in replication rates and fidelity among different viruses by generating chimeric RdRPs from poliovirus and coxsackievirus B3. We designed these chimeric polymerases by exchanging the fingers, pinky finger, or thumb domains. The results of biochemical, rapid-quench, and stopped-flow assays revealed that differences in biochemical activity map to individual modular domains of this polymerase. We found that the pinky finger subdomain is a major regulator of initiation and that the palm domain is the major determinant of catalytic rate and nucleotide discrimination. We further noted that thumb domain interactions with product RNA regulate translocation and that the palm and thumb domains coordinately control elongation complex stability. Several RdRP chimeras supported the growth of infectious poliovirus, providing insights into enterovirus species–specific protein–protein interactions required for virus replication.

scholarly journals Structure ofPlasmodium falciparumorotate phosphoribosyltransferase with autologous inhibitory protein–protein interactions

2015 ◽  
Vol 71 (5) ◽  
pp. 600-608 ◽  
Author(s):  
Shiva Kumar ◽  
Kalyanaraman Krishnamoorthy ◽  
Devaraja G. Mudeppa ◽  
Pradipsinh K. Rathod
Keyword(s):  
Protein Interactions ◽  
Active Sites ◽  
De Novo ◽  
Low Complexity ◽  
Specific Protein ◽  
Severe Form ◽  
Protein Protein Interactions ◽  
Inhibitory Protein ◽  
Pyrimidine Synthesis ◽  
Salvage Pathways

The most severe form of malaria is caused by the obligate parasitePlasmodium falciparum. Orotate phosphoribosyltransferase (OPRTase) is the fifth enzyme in thede novopyrimidine-synthesis pathway in the parasite, which lacks salvage pathways. Among all of the malariade novopyrimidine-biosynthesis enzymes, the structure ofP. falciparumOPRTase (PfOPRTase) was the only one unavailable until now.PfOPRTase that could be crystallized was obtained after some low-complexity sequences were removed. Four catalytic dimers were seen in the asymmetic unit (a total of eight polypeptides). In addition to revealing unique amino acids in thePfOPRTase active sites, asymmetric dimers in the larger structure pointed to novel parasite-specific protein–protein interactions that occlude the catalytic active sites. The latter could potentially modulatePfOPRTase activity in parasites and possibly provide new insights for blockingPfOPRTase functions.

The acute myeloid leukaemia market

2019 ◽  
Vol 19 (4) ◽  
pp. 233-234
Author(s):  
Jorrit Schaefer ◽  
Sorcha Cassidy ◽  
Rachel M. Webster
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acute Myeloid

Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome

2005 ◽  
Vol 44 (03) ◽  
pp. 107-117
Author(s):  
R. G. Meyer ◽  
W. Herr ◽  
A. Helisch ◽  
P. Bartenstein ◽  
I. Buchmann
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Primary Tumour ◽  
The Other ◽  
Haematopoietic Stem Cell ◽  
Other Hand ◽  
Primary Reduction ◽  
The One ◽  
Acute Myeloid

SummaryThe prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term diseasefree survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myeloablative conditioning before SCT.This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand.

Sign in / Sign up

Export Citation Format

Share Document