Small heterodimer partner

Function

The principal role of SHP appears to be repression of other nuclear receptors through association to produce a non-productive heterodimer. The protein has also been identified as a mediating factor in the metabolic circadian clock. Research shows that it interacts with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation. In addition, interaction with estrogen receptors has been demonstrated, leading to inhibition of function. Studies suggest that the protein represses nuclear hormone receptor-mediated transactivation via two separate steps: competition with coactivators and the direct effects of its transcriptional repressor function.

Structure and ligands

A crystal structure of the LBD-only SHP, generated by co-crystallisation with EID1, has been obtained. Instead binding to the usual AF-2 site, EID1 fills in the place of what is usually helix α1 of an LBD and makes SHP more soluble. The overall structure resembles the apo (ligandless) form of other LBDs. Some synthetic retinoid ligands can bind to SHP's LBD and promote its interaction with LXXLL-containing corepressors using the AF-2 site.

Interactions

Large and medium scale Y2H experiments as well as text mining of the NR literature have highlighted the important role of SHP in the Nuclear Receptor dimerization network and its relatively highly connected status, compared to other NRs.

Small heterodimer partner has been shown to interact with:

• Androgen receptor,
• Estrogen receptor alpha,
• Hepatocyte nuclear factor 4 alpha,
• Liver receptor homolog-1,
• Liver X receptor alpha,
• Peroxisome proliferator-activated receptor gamma,
• Retinoic acid receptor alpha,
• EID1,
• Retinoid X receptor alpha.

References

References

1. "Entrez Gene: NR0B2 nuclear receptor subfamily 0, group B, member 2".
2. (June 1998). "Structure and expression of the orphan nuclear receptor SHP gene". The Journal of Biological Chemistry.
3. (December 2005). "Transcriptional corepression by SHP: molecular mechanisms and physiological consequences". Trends in Endocrinology and Metabolism.
4. (September 2016). "Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice". Molecular Endocrinology.
5. (July 2007). "A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network". BMC Systems Biology.
6. (December 2001). "Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP". Biochemistry.
7. (March 2002). "The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells". Endocrinology.
8. (January 2000). "The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression". Molecular and Cellular Biology.
9. (January 2002). "Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner". The Journal of Biological Chemistry.
10. (September 2002). "The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity". Molecular Endocrinology.
11. (January 2002). "Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation". The Journal of Biological Chemistry.
12. (May 1996). "An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors". Science.
13. (October 1998). "Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner)". Molecular Endocrinology.
14. (January 2014). "Structural insights into gene repression by the orphan nuclear receptor SHP". Proceedings of the National Academy of Sciences of the United States of America.