7kht
From Proteopedia
The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor Steroidogenic Factor-1 (SF-1)
Structural highlights
DiseaseSTF1_HUMAN Defects in NR5A1 are a cause of 46,XY sex reversal type 3 (SRXY3) [MIM:612965. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype.[1] [2] [3] [4] Defects in NR5A1 are a cause of adrenocortical insufficiency without ovarian defect (ACIWOD) [MIM:184757. ACIWOD is characterized by severe 'slackness' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH.[5] Defects in NR5A1 are the cause of premature ovarian failure type 7 (POF7) [MIM:612964. An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol.[6] Defects in NR5A1 are the cause of spermatogenic failure type 8 (SPGF8) [MIM:613957. SPGF8 is an infertility disorder characterized by spermatogenesis failure and severe oligozoospermia.[7] FunctionSTF1_HUMAN Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation.[8] Publication Abstract from PubMedNuclear receptors are transcription factors that bind lipids, an event that induces a structural conformation of the receptor that favors interaction with transcriptional coactivators. The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) binds the signaling phosphoinositides PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3), and our previous crystal structures showed how the phosphoinositide headgroups regulate SF-1 function. However, what role the acyl chains play in regulating SF-1 structure remains unaddressed. Here, we used X-ray crystallography with in vitro binding and functional assays to examine how the acyl chains of PIP3 regulate human SF-1 ligand-binding domain structure and function. Altering acyl chain length and unsaturation regulates apparent binding of all tested phosphoinositides to SF-1. Mass spectrometry-based lipidomics data suggest C16 and C18 phospholipids preferentially associate with SF-1 expressed ectopically in bacteria. We then solved the 2.5 A crystal structure of SF-1 bound to dioleoyl PIP3(18:1/18:1) to compare it with a matched structure of SF-1 bound to dipalmitoyl PIP3(16:0/16:0). The dioleoyl-bound structure was severely disordered in a specific SF-1 region associated with pathogenic human polymorphisms and within the coactivator-binding region critical for SF-1 function while inducing increased sensitivity to protease digestion in solution. Validating these structural observations, in vitro functional studies showed dioleoyl PIP3 induced 6-fold poorer affinity of a peroxisome proliferator-activated receptor gamma coactivator 1-alpha coactivator peptide for SF-1 compared with dipalmitoyl PIP3. Together, these data suggest the chemical nature of the phosphoinositide acyl chains controls the ordered state of specific, clinically important structural regions in SF-1, regulating SF-1 function in vitro. The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1.,Bryant JM, Malabanan MM, Vanderloop BH, Nichols CM, Haratipour Z, Poon KT, Sherrod SD, McLean JA, Blind RD J Lipid Res. 2021;62:100081. doi: 10.1016/j.jlr.2021.100081. Epub 2021 Apr 29. PMID:33933440[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
