Single-point mutation in a conserved TPR domain of Hip disrupts enhancement of glucocorticoid receptor signaling

Place, Sean P.

doi:10.1007/s12192-010-0254-2

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…Notably, mutation L210S (L211S in human Hip) was previously identified in a screen for lossof-function mutants of human Hip (Place, 2011). In contrast to the above listed mutants, the double mutation H196S/E199A targeting the non-conserved intramolecular interface of the Hsp70N-HipM fusion protein had no effect on HipM activity (Fig.…”

Section: Hipm Mutation K D Value [µM]mentioning

confidence: 99%

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

Hartl

Bracher

2013

Nat Struct Mol Biol

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The Hsp70-interacting protein, Hip, cooperates with the chaperone Hsp70 in protein folding and prevention of aggregation. Hsp70 interacts with non-native protein substrates in an ATP-dependent reaction cycle regulated by J-domain proteins and nucleotide exchange factors (NEFs). Hip is thought to delay substrate release by slowing ADP dissociation from Hsp70. Here we present crystal structures of the dimerization domain and the tetratricopeptide repeat (TPR) domain of rat Hip. As shown in a cocrystal structure, the TPR core of Hip interacts with the Hsp70 ATPase domain through an extensive interface, to form a bracket that locks ADP in the binding cleft. Hip and NEF binding to Hsp70 are mutually exclusive, and thus Hip attenuates active cycling of Hsp70-substrate complexes. This mechanism explains how Hip enhances aggregation prevention by Hsp70 and facilitates transfer of specific proteins to downstream chaperones or the proteasome

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Section: Hipm Mutation K D Value [µM]mentioning

confidence: 99%

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

Hartl

Bracher

2013

Nat Struct Mol Biol

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Low resolution structural characterization of the Hsp70-interacting protein – Hip – from Leishmania braziliensis emphasizes its high asymmetry

Dores-Silva

Silva

Gomes

et al. 2012

Archives of Biochemistry and Biophysics

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The Hsp70 is an essential molecular chaperone in protein metabolism since it acts as a pivot with other molecular chaperone families. Several co-chaperones act as regulators of the Hsp70 action cycle, as for instance Hip (Hsp70-interacting protein). Hip is a tetratricopeptide repeat protein (TPR) that interacts with the ATPase domain in the Hsp70-ADP state, stabilizing it and preventing substrate dissociation. Molecular chaperones from protozoans, which can cause some neglected diseases, are poorly studied in terms of structure and function. Here, we investigated the structural features of Hip from the protozoa Leishmania braziliensis (LbHip), one of the causative agents of the leishmaniasis disease. LbHip was heterologously expressed and purified in the folded state, as attested by circular dichroism and intrinsic fluorescence emission techniques. LbHip forms an elongated dimer, as observed by analytical gel filtration chromatography, analytical ultracentrifugation and small angle X-ray scattering (SAXS). With the SAXS data a low resolution model was reconstructed, which shed light on the structure of this protein, emphasizing its elongated shape and suggesting its domain organization. We also investigated the chemical-induced unfolding behavior of LbHip and two transitions were observed. The first transition was related to the unfolding of the TPR domain of each protomer and the second transition of the dimer dissociation. Altogether, LbHip presents a similar structure to mammalian Hip, despite their low level of conservation, suggesting that this class of eukaryotic protein may use a similar mechanism of action.

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Mucosal host–microbe interactions associate with clinical phenotypes in inflammatory bowel disease

Bourgonje

Jansen

et al. 2022

Preprint

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Dysregulation of gut mucosal host-microbe interactions is a central feature of inflammatory bowel disease (IBD). To study tissue-specific interactions, we performed transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 696 intestinal biopsies derived from 353 patients with IBD and controls. Analysis of transcript-bacteria interactions identified six distinct groups of inflammation-related pathways that were associated with intestinal microbiota, findings we could partially validate in an independent cohort. An increased abundance of Bifidobacterium was associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides was associated with increased metallothionein signaling. In fibrostenotic Crohn's disease, a transcriptional network dominated by immunoregulatory genes associated with Lachnoclostridium bacteria in non-stenotic tissue. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes associated with Ruminococcaceae. Mucosal microbiota composition was associated with enrichment of specific intestinal cell types. Overall, we identify multiple host-microbe interactions that may guide microbiota-directed precision medicine.

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Single-point mutation in a conserved TPR domain of Hip disrupts enhancement of glucocorticoid receptor signaling

Abstract: The Hsp70-interacting protein Hip has been identified as a transient participant in the assembly of both glucocorticoid (GR) and progesterone receptor complexes.

Cited by 3 publications

References 12 publications

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

Low resolution structural characterization of the Hsp70-interacting protein – Hip – from Leishmania braziliensis emphasizes its high asymmetry

Mucosal host–microbe interactions associate with clinical phenotypes in inflammatory bowel disease

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