Integrated Structural Modeling of Full-Length LRH-1 Reveals Inter-domain Interactions Contribute to Receptor Structure and Function

Seacrist, Corey D.; Kuenze, Georg; Hoffmann, Reece M.; Moeller, Brandon E; Burke, John E.; Meiler, Jens; Blind, Raymond D.

doi:10.1016/j.str.2020.04.020

Cited by 31 publications

(51 citation statements)

References 93 publications

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“…3 A, B) typical for nuclear receptor ligand binding domains, distributed into three layers, with fully ordered helices 1 and 2 ( Fig. 3 C) typical for the subclass of nuclear receptors which SF-1 belongs (NR5A) ( 15 , 40 , 43 , 44 ). The 12 alpha helices end with the C-terminal helix 12, which helps form the site that binds the PGC1α coactivator peptide ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Those data suggest some form of interdomain communication must occur between the SF-1 ligand-binding domain (LBD) and DNA-binding domain (DBD), since the R255 amino acid is located in the LBD, but changes function of the DBD. We recently developed a structural model describing LBD-DBD communication for full length LRH-1 (NR5A2), a close homolog of SF-1 (NR5A1) (48). That model of LRH-1 shows LBD helix 2 is a key site for an interaction between the LBD and DBD, and that disrupting the interdomain interaction on the LBD side, alters DNA-binding on the DBD side of the interface (48).…”

Section: Discussionmentioning

confidence: 99%

“…We recently developed a structural model describing LBD–DBD communication for full-length LRH-1 ( NR5A2 ), a close homolog of SF-1 ( NR5A1 ) ( 44 ). That model of LRH-1 shows LBD helix 2 is a key site for an interaction between the LBD and DBD, and disrupting the interdomain interaction on the LBD side alters DNA-binding on the DBD side of the interface ( 44 ). Although three-dimensional homology between full-length SF-1 and LRH-1 proteins is unclear, it is tempting to speculate that 2–3 loop disorder induced by acyl chain composition could translate acyl chain occupancy information from the LBD to the DBD, altering SF-1 DNA-binding and transactivation, that the R255L mutant fails to shift DNA oligos is consistent with a model in which the stability of the LBD–DBD interaction is regulated by acyl-chain occupancy of the LBD in WT SF-1, and that the R255L mutant may lose function, in part, by preventing full LBD–DBD communication via the 2–3 loop.…”

Section: Discussionmentioning

confidence: 99%

“…In phosphoinositide mass spectrometry studies conducted in mammalian cells, the C36:2 MS peak can report dioleoyl species which is frequently observed in mammalian cells (46). As expected, the crystal structure of SF-1 bound to dioleoyl J o u r n a l P r e -p r o o f PIP3(18:1/18:1) adopts a 12-helical bundle structure (Fig 3A,B) typical for nuclear receptor ligand binding domains, distributed into three layers, with fully ordered helices 1 and (Fig 3C) typical for the sub-class of nuclear receptors which SF-1 belongs (NR5A) (15,43,47,48). The 12 alpha-helices end with the Cterminal helix 12, which helps form the site that binds the PGC1α coactivator peptide (Fig 3D).…”

Section: Sf-1 Lbd Ectopically Expressed In Bacteria Is Bound By C16 and C18 Acyl Phospholipidsmentioning

confidence: 99%

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The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1

Bryant¹,

Malabanan²,

Vanderloop³

et al. 2021

Journal of Lipid Research

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sf-1 Lbd Ectopically Expressed In Bacteria Is Bound By C16 and C18 Acyl Phospholipidsmentioning

confidence: 99%

See 2 more Smart Citations

The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1

Bryant¹,

Malabanan²,

Vanderloop³

et al. 2021

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

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“…Using similar techniques, Seacrist et al . found that monomeric NR LRH1 adopted a more globular complex on DNA such that the LRH1DBD transmitted information to the LRH1LBD [47]. In contrast, our studies suggest that RORγ becomes elongated upon DNA recognition effectively uncoupling the two domains.…”

Section: Discussionmentioning

confidence: 62%

Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

Strutzenberg

Novick

Garcia-Ordoñez

et al. 2021

Preprint

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The retinoic acid receptor-related orphan receptorγ (RORγ) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of RORγ is far from complete. Like most nuclear receptors, RORγ must recruit coregulatory protein to enact the RORγ target gene program. To date, a majority of structural studies have been focused exclusively on the RORγ ligand-binding domain and the ligand-dependent recruitment of small peptide segments of coregulators. Herein, we examine the ligand-dependent assembly of full length RORγ:coregulator complexes on cognate DNA response elements using structural proteomics and small angle x-ray scattering. The results from our studies suggest that RORγ becomes elongated upon DNA recognition, preventing long range interdomain crosstalk. We also determined that the DNA binding domain adopts a sequence-specific conformation, and that coregulatory proteins may be able to sense the ligand- and DNA-bound status of RORγ. We propose a model where ligand-dependent coregulator recruitment may be influenced by the sequence of the DNA to which RORγ is bound. Overall, the efforts described herein will illuminate important aspects of full length RORγ and monomeric orphan nuclear receptor target gene regulation through DNA-dependent conformational changes.

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NR5A2 promotes malignancy progression and mediates the effect of cisplatin in cutaneous squamous cell carcinoma

Ye,

Ya‐xuan,

Shan‐shan

et al. 2024

Immunity Inflam & Disease

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IntroductionNuclear receptor subfamily five group A member two (NR5A2) plays a key role in the development of many tumor types, while it is uncertain in cutaneous squamous cell carcinoma (cSCC). The aim of this work was to determine the role of NR5A2 in cSCC proliferation, and to determine whether NR5A2 mediates the effect of cisplatin in cSCC.MethodsWe performed a systematic study of existing data and conducted a preliminary bioinformatics analysis of NR5A2 expression in cSCC using bioinformatics databases. Immunohistochemical staining was performed on cSCC tissues of seven patients to study NR5A2 expression. NR5A2 expression was examined in human keratin‐forming cells (HaCaT) and human cSCC cells (A431, Colo‐16, SCL‐1, SCL‐2, and HSC‐5). Stable A431 and SCL‐2 cell lines consisting of sh‐RNA‐NR5A2 were constructed to detect changes in cell proliferation, cell cycle, apoptosis, and to determine the key proteins in the Wnt/β‐catenin pathway. We also investigated changes in the effects of cisplatin on cSCC cells by CCK‐8, clone formation assay, and Flow apoptosis assay after NR5A2 knockdown.ResultsNR5A2 showed enhanced expression in cSCC tissues than in healthy tissues. Downregulation of NR5A2 in cSCC cells led to the formation of a less malignant phenotype. In contrast, the proliferative capacity of the cSCC cells was enhanced posttreatment with RJW100, an NR5A2 agonist. Additionally, NR5A2 knockdown led to a decrease in the expression level of the proteins in the Wnt/β‐catenin pathway, and this inhibition was reversed by LiCl and recombinant antibody, Wnt3a. Moreover, NR5A2 knockdown resulted in diminished proliferative capacity and increased apoptotic cells after the addition of cisplatin.ConclusionNR5A2 plays a crucial role in the progression of cSCC, and the Wnt/β‐catenin signaling pathway may be involved in the regulation of NR5A2‐mediated cSCC. Knockdown of NR5A2 enhanced both the proliferation inhibiting and apoptosis promoting effects of cisplatin on cSCC.

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Integrated Structural Modeling of Full-Length LRH-1 Reveals Inter-domain Interactions Contribute to Receptor Structure and Function

Cited by 31 publications

References 93 publications

The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1

The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1

Conformational Changes of RORγ During Response Element Recognition and Coregulator Engagement

NR5A2 promotes malignancy progression and mediates the effect of cisplatin in cutaneous squamous cell carcinoma

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