7KHT

The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor Steroidogenic Factor-1 (SF-1)

Summary for 7KHT

• Entry DOI: 10.2210/pdb7kht/pdb
• Descriptor: Steroidogenic factor 1, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha peptide, (2S)-3-{[(S)-{[(1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonooxy)cyclohexyl]oxy}(hydroxy)phosphoryl]oxy}propane-1,2-diyl (9E,9'E)di-octadec-9-enoate, ... (4 entities in total)
• Functional Keywords: pi(3, 4, 5)p3 acyl chains, acyl chain length, acyl chain induced conformational change, nuclear pip2, nuclear pip3, nuclear receptor, lipid binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30530.31

Authors

Blind, R.D. (deposition date: 2020-10-22, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

Bryant, J.M.,Malabanan, M.M.,Vanderloop, B.H.,Nichols, C.M.,Haratipour, Z.,Poon, K.T.,Sherrod, S.D.,McLean, J.A.,Blind, R.D.
The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor steroidogenic factor-1.
J.Lipid Res., 62:100081-100081, 2021

PubMed Abstract: Nuclear 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 Å 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.

PubMed: 33933440
DOI: 10.1016/j.jlr.2021.100081

Experimental method

X-RAY DIFFRACTION (2.504 Å)