Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Solomon, Isaac H.; Hager, Janet; Safi, Rachid; McDonnell, Donald P.; Redinbo, Matthew R.; Ortlund, Eric A.

doi:10.1016/j.jmb.2005.10.009

Cited by 53 publications

(66 citation statements)

References 57 publications

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“…In particular, regulation of the CYP19A gene encoding aromatase, which converts androgens to estrogens, gives LRH-1 a pivotal role in estrogen signaling (25-28). Similar to Dax-1, LRH-1 is indispensable to maintaining the pluripotent state of embryonic stem cells (29).Unlike other nuclear receptors that function as homodimers or heterodimers, LRH-1 binds DNA with high affinity as a monomer (30,31). In contrast to hormone-controlled nuclear receptors, physiological ligands for LRH-1 have not yet been identified, consistent with the fact that NR5A receptors activate reporter gene transcription in the absence of exogenously added ligands (32).…”

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confidence: 97%

“…Unlike other nuclear receptors that function as homodimers or heterodimers, LRH-1 binds DNA with high affinity as a monomer (30,31). In contrast to hormone-controlled nuclear receptors, physiological ligands for LRH-1 have not yet been identified, consistent with the fact that NR5A receptors activate reporter gene transcription in the absence of exogenously added ligands (32).…”

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confidence: 99%

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The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

Sablin¹,

Woods²,

Krylova

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The Dax-1 protein is an enigmatic nuclear receptor that lacks an expected DNA binding domain, yet functions as a potent corepressor of nuclear receptors. Here we report the structure of Dax-1 bound to one of its targets, liver receptor homolog 1 (LRH-1). Unexpectedly, Dax-1 binds to LRH-1 using a new module, a repressor helix built from a family conserved sequence motif, PCFXXLP. Mutations in this repressor helix that are linked with human endocrine disorders dissociate the complex and attenuate Dax-1 function. The structure of the Dax-1:LRH-1 complex provides the molecular mechanism for the function of Dax-1 as a potent transcriptional repressor.Dax-1 ͉ LRH-1 ͉ nuclear receptor ͉ regulation ͉ structure T he orphan nuclear receptor DAX-1/Dax-1 (dosage-sensitive sex-reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1) (1) is well known for its role in human pathophysiology. Duplication of the DAX-1 gene causes phenotypic sex reversal in XY individuals (2), and mutations in DAX-1 are responsible for adrenal hypoplasia congenita, an inherited disorder of adrenal gland development (3). During embryogenesis, Dax-1 functions to direct cell differentiation in testes and adrenal tissues (1). In adult physiology, Dax-1 acts as a global repressor of many nuclear receptors, including SF-1, Nur77, ERR␥, ER, AR, PR, and LRH-1 (4-13). Dax-1 also is indispensable to maintaining the pluripotent state of embryonic stem cells (14,15).There is a little information on either the structure or regulatory mechanisms of Dax-1. Dax-1 belongs to a unique family of nuclear receptors (NR0B1) that lack the essential DNA binding domain. Instead, the human Dax-1 N terminus consists of three sequence repeats that include the LXXL/ML motif (''LXXL/ML boxes'' 1-3) (16). This unique N-terminal extension is thought to play a role in subcellular distribution and nuclear localization of . No homologues for the N-terminal region of Dax-1 are known, but its C-terminal domain is a clear homologue of the nuclear receptor ligandbinding domain (LBD) (1). To date, no hormone for Dax-1 has been identified, and the mechanism of its function as corepressor remains under debate (4, 5, 7-9, 12, 18-20). The elucidation of Dax-1 mechanisms has been frustrated by a lack of highresolution structural information. Here we report the first structure of Dax-1 bound to its physiological target, nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2).LRH-1 was first discovered in the liver and intestine, where it regulates genes controlling bile acid synthesis and cholesterol homeostasis (21-24). Recently, LRH-1 was found in human steroidogenic tissues and was shown to activate transcription of genes encoding steroidogenic enzymes (25). In particular, regulation of the CYP19A gene encoding aromatase, which converts androgens to estrogens, gives LRH-1 a pivotal role in estrogen signaling (25-28). Similar to Dax-1, LRH-1 is indispensable to maintaining the pluripotent state of embryonic stem cells (29).Unlike other nuclear receptors that func...

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mentioning

confidence: 97%

mentioning

confidence: 99%

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

Sablin¹,

Woods²,

Krylova

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…ER) to palindromes of the AGGTCA motif or to direct repeats of the AGGTCA motif as heterodimers with retinoid X receptor-(RXR ) [11]. By contrast, members of the Ftz-F1 subfamily bind to sequences having a 5' extension to the NR DNA binding motif as monomers, with the Ftz-F1 box targeting the 5'-YCA extension to the NR DNA binding motif [12], where Y is C or T. Until recently classified as orphan receptors, structural studies have shown that LRH-1 and SF-1 bind phosphatidyl inositols, with their binding being required for maximal activity [13][14][15]. LRH-1 plays important roles in metabolism, being involved in the regulation of reverse cholesterol transport, lipid and cholesterol absorption, bile acid homeostasis and steroidogenesis [10].…”

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confidence: 99%

The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

Thiruchelvam

Lai

Hua

et al. 2010

Breast Cancer Res Treat

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“…Structural characterization of the SF-1 (Little et al, 2005) and LRH-1 (Solomon et al, 2005) DBDs has shown that these nuclear receptors contain a unique Ftz-F1 helix carboxy-terminal to the core DBD and C-terminal extensions observed in most nuclear receptors. This helix acts as a secondary determinant for DNA affinity and is critical for proper function.…”

Section: Structures and Signals That Regulate Local And Endocrinementioning

confidence: 99%

“…Simultaneously, 3-D structures of key regulating hormones including FSH and its receptor (Fan andHendrickson, 2005,Fox et al, 2001) and activin together with both its binding receptor (ActRIIA/B) (Thompson et al, 2003,Greenwald et al, 2004 and bioneutralizing regulating partner (follistatin) ,Harrington et al, 2006 have been solved giving new glimpses into the biology they control. Inside the granulosa cell, regulating enzymes such as the human C17 aromatase have been modeled and the co-regulators of aromatase and other genes, LRH-1 and SF-1 have been solved at the molecular level (Solomon et al, 2005,Little et al, 2005.…”

Section: Introductionmentioning

confidence: 99%

The structures that underlie normal reproductive function

Lerch¹,

Xu²,

Jardetzky³

et al. 2007

Molecular and Cellular Endocrinology

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The mechanisms and physiology of reproductive function have fascinated scientists throughout time. Recent cellular and molecular level structural studies have provided unprecedented insights into reproductive systems and signaling networks. This 'cutting edge' editorial provides a recent example in each of these areas, namely, the anatomical integrity of the follicle, the molecular structure of activin with its binding partners and the molecular regulation of inhibin. These three examples of structure informing function help explain reproductive health and may provide solutions to reproductive disease.

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Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Cited by 53 publications

References 57 publications

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

The structures that underlie normal reproductive function

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