NucleaRDB: Extraction of mutation data from the literature

2005, NucleaRDB.

This data was extracted from Medline abstracts and full texts (when available) in an automated manner.

The table below describes the selected point mutation and provides links to other documents. The sentence(s) where the point mutation T350M was found are listed after the table.

The mutated residues are also indicated in the family sequence alignments and hyperlinked to the corresponding mutation pages.

Point mutation T350M in NR1I3_MOUSE

Point mutation:	T350M
Cited point mutation:	Thr350Met,Thr350
Domain:	LBD HELIX 12
General numbering (NucleaRDB):	1245
Protein:	NR1I3_MOUSE (Nr1i3,Ca)	Swiss-Prot Cross-reference table Family page
Protein isoforms	2
Other point mutations / same protein / same position	Point mutations at position 350 in NR1I3_MOUSE
Other point mutations / same protein	List of mutations in NR1I3_MOUSE
Family alignments	1I3 Constitutive Androstane alpha (CAR1) 1I Vitamin D3-like (VDR,PXR,CAR) 1 Thyroid hormone like (TR,RAR,ROR,PPAR,VDR
Other point mutations / same position	Position 350 in 1I3 Constitutive Androstane alpha (CAR1) family Position 410 in 1I Vitamin D3-like (VDR,PXR,CAR) family Position 398 in 1 Thyroid hormone like (TR,RAR,ROR,PPAR,VDR family
Reference:	Molecular determinants of steroid inhibition for the mouse constitutive androstane receptor. Jyrkkarinne J, Makinen J, Gynther J, Savolainen H, Poso A, Honkakoski P J Med Chem 2003 Oct 23;46(22):4687-95.	Medline
Other point mutations / same article	List
Text source	HTML full text
Validation status	Not yet checked

Relevant sentences:

Thr350Met

The response to TCPOBOP was decreased but not completely abolished with Thr350Met mutant
Figure 5C indicates that TCPOBOP enhanced SRC-1 interaction with mCAR and Thr350Ala mutant , to a lesser extent with Thr350Met mutant but not with hCAR
Interestingly , SRC-1 interaction was enhanced by progesterone with Thr350Met mutant only , in agreement with data in Figure 5A
In support of this idea , androstanol was recently shown to enhance interactions of the corepressor SMRT between mCAR with a mammalian two-hybrid assay in CV-1 cells.33 Ueda et al. reported that testosterone and progesterone inhibited mCAR depending on type of residue 350 , and thus this residue would directly regulate steroid-responsiveness of mCAR.29 They also showed that overexpression of SRC-1 prevented the suppression by progesterone of wild-type mCAR but not Thr350Met mutant , which implied that progesterone might inhibit mCAR through dissociation of SRC-1
These distinct orientations may explain why progesterone enhanced interactions of the Thr350Met mutant with both NCoR and SRC-1

Thr350

The importance of residues 201-263 appears to contrast with the recent report that residue 350 in helix 12 regulates the inhibition of mCAR by steroids.29 Substitution of Thr350 with Met , the corresponding residue in hCAR , abolished the inhibition by progesterone and testosterone
However , the response to the potent inhibitor androstenol was not measured in that study.29 Figure 5A indicates that mutation of Thr350 to Ala did not change the response of mCAR to steroids or TCPOBOP
Substitution of Thr350 with Met did not affect the inhibition by androstenol or testosterone
The response to TCPOBOP was decreased but not completely abolished with Thr350Met mutant
Figure 5C indicates that TCPOBOP enhanced SRC-1 interaction with mCAR and Thr350Ala mutant , to a lesser extent with Thr350Met mutant but not with hCAR
Interestingly , SRC-1 interaction was enhanced by progesterone with Thr350Met mutant only , in agreement with data in Figure 5A
In support of this idea , androstanol was recently shown to enhance interactions of the corepressor SMRT between mCAR with a mammalian two-hybrid assay in CV-1 cells.33 Ueda et al. reported that testosterone and progesterone inhibited mCAR depending on type of residue 350 , and thus this residue would directly regulate steroid-responsiveness of mCAR.29 They also showed that overexpression of SRC-1 prevented the suppression by progesterone of wild-type mCAR but not Thr350Met mutant , which implied that progesterone might inhibit mCAR through dissociation of SRC-1
Our data also indicate that the role of residue 350 in steroid inhibition is limited: the Thr350Ala mutant behaved exactly like the wild-type mCAR , and the responses to androstenol or testosterone are not changed by either Ala or Met mutations
The striking difference was that conversion of Thr350 to Met changed progesterone to an activator in both mammalian and yeast assays
These distinct orientations may explain why progesterone enhanced interactions of the Thr350Met mutant with both NCoR and SRC-1
Moreover , mCAR lacking the entire helix 12 was still able to recruit NCoR in response to androstenol and also testosterone and progesterone , suggesting that amino acids in helix 12 including Thr350 are not essential for steroid recognition
Thus , they would not be directly linked to specific steroid recognition by mCAR , which was the focus of this investigation and the suggested role for the residue Thr350.29 On the basis of a homology model built on the pregnane X receptor , it was hypothesized that androstenol might bind to the mCAR coactivator surface (and not to the ligand-binding pocket) due to its mimicry of hydrophobic residues Leu352 , Leu353 , Ile356 , and Cys357 in helix 12

F.Horn (nucleardbcmbi.kun.nl), 21-Apr-2005