ABCD1 p.Trp679Arg
| Predicted by SNAP2: | A: D (91%), C: D (85%), D: D (95%), E: D (95%), F: D (85%), G: D (95%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (91%), V: D (91%), Y: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, Y: D, |
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[hide] Involvement of the carboxyl-terminal region of the... PLoS One. 2014 Aug 13;9(8):e104892. doi: 10.1371/journal.pone.0104892. eCollection 2014. Chuang CY, Chen LY, Fu RH, Chen SM, Ho MH, Huang JM, Hsu CC, Wang CC, Chen MS, Tsai RT
Involvement of the carboxyl-terminal region of the yeast peroxisomal half ABC transporter Pxa2p in its interaction with Pxa1p and in transporter function.
PLoS One. 2014 Aug 13;9(8):e104892. doi: 10.1371/journal.pone.0104892. eCollection 2014., [PMID:25118695]
Abstract [show]
BACKGROUND: The peroxisome is a single membrane-bound organelle in eukaryotic cells involved in lipid metabolism, including beta-oxidation of fatty acids. The human genetic disorder X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene (encoding ALDP, a peroxisomal half ATP-binding cassette [ABC] transporter). This disease is characterized by defective peroxisomal beta-oxidation and a large accumulation of very long-chain fatty acids in brain white matter, adrenal cortex, and testis. ALDP forms a homodimer proposed to be the functional transporter, whereas the peroxisomal transporter in yeast is a heterodimer comprising two half ABC transporters, Pxa1p and Pxa2p, both orthologs of human ALDP. While the carboxyl-terminal domain of ALDP is engaged in dimerization, it remains unknown whether the same region is involved in the interaction between Pxa1p and Pxa2p. METHODS/PRINCIPAL FINDINGS: Using a yeast two-hybrid assay, we found that the carboxyl-terminal region (CT) of Pxa2p, but not of Pxa1p, is required for their interaction. Further analysis indicated that the central part of the CT (designated CT2) of Pxa2p was indispensable for its interaction with the carboxyl terminally truncated Pxa1_NBD. An interaction between the CT of Pxa2p and Pxa1_NBD was not detected, but could be identified in the presence of Pxa2_NBD-CT1. A single mutation of two conserved residues (aligned with X-ALD-associated mutations at the same positions in ALDP) in the CT2 of the Pxa2_NBD-CT protein impaired its interaction with Pxa1_NBD or Pxa1_NBD-CT, resulting in a mutant protein that exhibited a proteinase K digestion profile different from that of the wild-type protein. Functional analysis of these mutant proteins on oleate plates indicated that they were defective in transporter function. CONCLUSIONS/SIGNIFICANCE: The CT of Pxa2p is involved in its interaction with Pxa1p and in transporter function. This concept may be applied to human ALDP studies, helping to establish the pathological mechanism for CT-related X-ALD disease.
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No. Sentence Comment
81 We indeed found ALD disease-related point mutations in the CT2 of ALDP: W679R and L684P.
X
ABCD1 p.Trp679Arg 25118695:81:72
status: NEW170 The conserved amino acids (Y726 and F731) in the CT2 of Pxa2p corresponded to the point mutations W679R and L684P in ALD.
X
ABCD1 p.Trp679Arg 25118695:170:98
status: NEW199 The mutations Y726L and F731A in the CT2 of Pxa2p, shown in the present study to disrupt Pxa1_NBD/Pxa2_NBD interaction, correspond to the mutations W679R and L684P in the CT2 of human ALDP.
X
ABCD1 p.Trp679Arg 25118695:199:148
status: NEW200 From the records in the human X-ALD database (http://www.x-ald.nl/), we found that W679R was the first missense mutation discovered in exon 10 of the ALDP gene [37].
X
ABCD1 p.Trp679Arg 25118695:200:83
status: NEW215 doi:10.1371/journal.pone.0104892.g009 Y726L and F731A in Pxa2p on its protein interaction with Pxa1p may provide a significant reference for ALDP protein with W679R and L684P mutations.
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ABCD1 p.Trp679Arg 25118695:215:160
status: NEW216 Thus, the effects of the W679R and L684P mutations in ALDP on protein-protein interaction are worth determining in future.
X
ABCD1 p.Trp679Arg 25118695:216:25
status: NEW346 Korenke GC, Krasemann E, Meier V, Beuche W, Hunneman DH, et al. (1998) First missense mutation (W679R) in exon 10 of the adrenoleukodystrophy gene in siblings with adrenomyeloneuropathy.
X
ABCD1 p.Trp679Arg 25118695:346:96
status: NEW