Structural and functional studies of the Leishmania braziliensis SGT co-chaperone indicate that it shares structural features with HIP and can interact with both Hsp90 and Hsp70 with similar affinities

Coto, Amanda L. S.; Seraphim, Thiago Vargas; Batista, Fernanda Aparecida Heleno; Dores-Silva, Paulo R.; Barranco, Ana Beatriz F.; Teixeira, Felipe Roberti; Gava, Lisandra M.; Borges, Júlio César

doi:10.1016/j.ijbiomac.2018.06.123

Cited by 14 publications

(14 citation statements)

References 80 publications

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“…As noted above, for STI1 these domains are critical for coordinated hand-off between Hsp70 and Hsp90 homologs (58) as well as coordinating the simultaneous binding of two HSPs. Both Sgt2 and the cochaperone Hip coordinate pairs of TPR and STI1 domains by forming stable dimers via their N-terminal dimerization domains (59). With evidence for a direct role of the carboxylate clamp in the TPR domain of Sgt2 for TA client binding now clear (21), one can speculate that the two TPR domains may facilitate TA client entry into various pathways that use multiple HSPs.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2

Lin

Fry²,

Saladi³

et al. 2021

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2

Lin

Fry²,

Saladi³

et al. 2021

Journal of Biological Chemistry

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“…The SGT orthologue in L. donovani is an essential protein for L. donovani promastigote growth and viability (165). LdSGT was shown to form large, stable complexes that included Hsp83, Hsp70, HIP, HOP, J-proteins, and Hsp100 (165), whereas recombinant L. braziliensis SGT was shown to interact with both LbHsp90 and HsHsp70-1A (166). Therefore, the orthologous proteins in T. b. brucei and T. b. gambiense may have developed the same activity and assist in the formation of the T. brucei Hsp83 chaperone system.…”

Section: Small Glutamine-rich Tpr-containing Protein (Sgt)mentioning

confidence: 99%

The Hsp90 chaperone system from the African trypanosome,Trypanosoma brucei

Boshoff

Jamabo

Bentley

et al. 2021

Preprint

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African Trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei ( T. brucei ) and is spread by the tsetse fly in sub-Saharan Africa. The disease is fatal if left untreated and the currently approved drugs for treatment are toxic and difficult to administer. The trypanosome must survive in the insect vector and its mammalian host, and to adapt to these different conditions, the parasite relies on molecular chaperones called heat shock proteins. Heat shock proteins mediate the folding of newly synthesized proteins as well as prevent misfolding of proteins under normal conditions and during stressful conditions. Heat shock protein 90 (Hsp90) is one of the major molecular chaperones of the stress response at the cellular level. It functions with other chaperones and co-chaperones and inhibition of its interactions is being explored as a potential therapeutic target for numerous diseases. This study provides an in-silico overview of Hsp90 and its co-chaperones in both T. brucei brucei and T. brucei gambiense in relation to human and other kinetoplastid parasites . The evolutionary, functional, and structural analyses of Hsp90 were also shown. The updated information on Hsp90 and its co-chaperones from recently published proteomics on T. brucei was examined for the different life cycle stages and subcellular localisations. The results show a difference between T. b. brucei and T. b. gambiense with T. b. brucei encoding 12 putative Hsp90 genes, 10 of which are cytosolic and located on a single chromosome while T. gambiense encodes 5 Hsp90 genes, 3 of which are located in the cytosol. Eight putative co-chaperones were identified in this study, 6 TPR-containing and 2 non-TPR-containing co-chaperones. This study provides an updated context for studying the biology of the African trypanosome and evaluating Hsp90 and its interactions as potential drug targets.

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“…As noted above, for Sti1 these domains are critical for client-processing and coordinated hand-off between Hsp70 and Hsp90 homologs [58] as well as coordinating the simultaneous binding of two heat shock proteins. Both Sgt2 and the co-chaperone Hip coordinate pairs of TPR and STI1 domains by forming stable dimers via their N-terminal dimerization domains [59]. With evidence for a direct role of the carboxylate-clamp in the TPR domain of Sgt2 for client-binding now clear [21], one can speculate that the two TPR domains may facilitate TA client entry into various pathways that use multiple heat shock proteins.…”

Section: Sgt2-c Preferentially Binds To Tmds With a Hydrophobic Facementioning

confidence: 99%

The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix

Lin

Fry

Saladi

et al. 2019

Preprint

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The correct targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) is critical for cellular homeostasis. The mammalian protein SGTA, and its fungal homolog Sgt2 (Sgt2/A), binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2/A binding to TA clients. We establish that the Sgt2/A C-terminal region is conserved but flexible, sufficient for client binding, and has functional and structural similarity to the DP domains of Sti1. A molecular model for Sgt2/A-C reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA clients with hydrophobic faces and a minimal length of 11 residues. Finally, we show that a hydrophobic face metric improves the predictions for TA localization in vivo. The structure and binding mechanism positions Sgt2/A into a broader class of helical-hand domains that reversibly bind hydrophobic clients.

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Structural and functional studies of the Leishmania braziliensis SGT co-chaperone indicate that it shares structural features with HIP and can interact with both Hsp90 and Hsp70 with similar affinities

Cited by 14 publications

References 80 publications

Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2

Molecular basis of tail-anchored integral membrane protein recognition by the cochaperone Sgt2

The Hsp90 chaperone system from the African trypanosome,Trypanosoma brucei

The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix

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