1,721,099 research outputs found
The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: Pathological exploitation of proteostasis machinery
No full textThis dataset represents the documentation and supporting information for the following published review article submitted to Frontiers in Molecular Biosciences:
"The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: Pathological exploitation of proteostasis machinery".
This was an invited contribution to the following Section and Research Topic:
Section: Protein Folding, Misfolding and Degradation;
Research Topic: Guardians of Protein Homeostasis (Proteostasis) in Health, Disease and Aging.
The intracellular malaria parasite, Plasmodium falciparum, has evolved the capacity to invade and transform mature human erythrocytes into vehicles of pathology. The parasite completely remodels the host cell by exporting numerous malaria proteins, including molecular chaperones and co-chaperones. The P. falciparum JDP (PfJDP) family is highly expanded with at least 49 members, and just under half predicted to be exported. The evidence suggests that there is an intricate network of PfJDP interactions with the exported malarial Hsp70 (PfHsp70-x) and human Hsp70, which appears to be important for the trafficking of key malarial virulence factors. This review critically evaluates the current understanding of the role of exported malarial JDPs in fine-tuning human and malarial Hsp70s, so as to re-set proteostasis for pathological purposes
In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: A drug repurposing strategy against malaria
No full textThis dataset has all the documentation and data associated with an article published in Frontiers in Molecular Biosciences entitled "In silico identification of modulators of J domain protein-Hsp70 interactions in Plasmodium falciparum: A drug repurposing strategy against malaria” by Harpreet Singh, Shaikha Y. Almaazmi, Tanima Dutta, Robert A. Keyzers, Gregory L. Blatch. The article contributes new information and understanding regarding malarial co-chaperone-chaperone complexes as drug targets for anti-malarial drug discovery. The article has been published in the section on “Biological Modeling and Simulation" in Frontiers in Molecular Biosciences
Role of the Hsp40 Family of Proteins in the Survival and Pathogenesis of the Malaria Parasite
No full textRole of the Hsp40 family of proteins in the survival and pathogenesis of the malaria parasite
No full textHsp70/Hsp90 organising protein (Hop): Beyond interactions with chaperones and prion proteins
No full textThe Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrPC
Role of the J Domain Protein Family in the Survival and Pathogenesis of Plasmodium falciparum
No full textPlasmodium falciparum has dedicated an unusually large proportion of its genome to molecular chaperones (2% of all genes), with the heat shock protein 40 (Hsp40) family (now called J domain proteins, JDPs) exhibiting evolutionary radiation into 49 members. A large number of the P. falciparum JDPs (PfJDPs) are predicted to be exported, with certain members shown experimentally to be present in the erythrocyte cytosol (PFA0660w and PFE0055c) or erythrocyte membrane (ring-infected erythrocyte surface antigen, RESA). PFA0660w and PFE0055c are associated with an exported plasmodial Hsp70 (PfHsp70-x) within novel mobile structures called J-dots, which have been proposed to be dedicated to the trafficking of key membrane proteins such as erythrocyte membrane protein 1 (PfEMP1). Well over half of the PfJDPs appear to be essential, including the J-dot PfJDP, PFE0055c, while others have been found to be required for growth under febrile conditions (e.g. PFA0110w, the ring-infected erythrocyte surface antigen protein [RESA]) or involved in pathogenesis (e.g. PF10_0381 has been shown to be important for protrusions of the infected red blood cell membrane, the so-called knobs). Here we review what is known about those PfJDPs that have been well characterised, and may be directly or indirectly involved in the survival and pathogenesis of the malaria parasite
Blatch, Gregory Lloyd (Prof)
No full textDepartment of Biochemistry & Microbiology Gregory L Blatch ORCID 0000-0003-0778-8577 Vice-Chancellor’s Distinguished Senior Research Award 2006. Professor Gregory Blatch Top 30 Rhodes Researchers 2008, 2009</a
The characterisation of trypanosomal type 1 DnaJ-like proteins
Get PDFTrypanosomes are protozoans, of which many are parasitic, and possess complex lifecycles
which alternate between mammalian and arthropod hosts. As is the case with most
organisms, molecular chaperones and heat shock proteins are encoded within the
genomes of these protozoans. These proteins are an integral part of maintaining the
structural integrity of proteins during normal and stress conditions. Heat shock protein 40
(Hsp40) is a co-chaperone of heat shock protein 70 (Hsp70) and in some cases can act as
a chaperone. These proteins work together to bind non-native polypeptide structures to
prevent unfolded protein aggregrate formation in times of stress, translocate proteins
across organelle membranes, and transport unsalvageable proteins to proteolytic
degradation by the cellular proteasome. Hsp40s are divided into four types based on their
domain structure.
Analysis of the nuclear genomes of eight trypanosomatid species revealed that less than
10 of the approximate 70 Hsp40 sequences per genome were Type 1 Hsp40s, many of
which contained putative orthologues in the other seven trypanosomatid genomes. One of
these Type 1 Hsp40s from T b. brucei, Trypanosoma brucei DnaJ 2 (Tbj2), was
functionally characterised in T brucei brucei. RNA interference knockdown of
expression in T brucei brucei showed that cells deficient in Tbj2 displayed a severe
inhibition of the growth of the cell population. The levels of the Tbj2 protein population
in T brucei brucei cells increases after exposure to 42°c and the protein was found to
have a generalized cytoplasmic subcellular localization at 37°c. These findings provide
evidence that Tbj2 is an orthologue of Yeast DnaJ 1 (Y dj l), an essential S. cerevisiae protein.
Hsp40s interact with their partner Hsp70s through their J-domain. The amino acids of the
J-domain important for a functional interaction with Hsp70 were examined in
Trypanosoma cruzi DnaJ 2 (Tcj2) (the orthologue of Tbj2) and T cruzi DnaJ protein 3
(Tcj3) by testing their ability to substitute for Y dj l in Saccharomyces cerevisae and for
DnaJ in Escherichia coli. In both systems, the positively charged amino acids of Helix II and III of the J-domain disrupted the functional interaction of these Hsp40s with their
partner Hsp70s. Substitutions in Helix I and IV of the J-domains of Tcj2 and Tcj3
produced varied results in the two different systems, possibly suggesting that these
helices serve to define with which Hsp70s a given Hsp40 can interact.
The inability of an Hsp40 and an Hsp70 to interact functionally does not necessarily
mean a total absence of physical interaction between these proteins. The amino acid
substitution of the histidine in the HPD motif (H34Q) of the J-domain of Tcj2 and Tcj3
removed the ability of these proteins to interact functionally with S. cerevisiae Hsp70
(Ssal) in vivo. However, preliminary binding studies using the quartz crystal
microbalance with dissipation monitoring (QCM-D) show that Tcj2 and Tcj2(H34Q)
both physically interact with M sativa Hsp70 in vitro.
This study is the first report to provide evidence that certain trypanosoma! Type 1 Hsp40s
are essential proteins. Futhermore, the interaction of these Hsp40s with Hsp70 identified
important features of the functional interface of this chaperone machinery
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