Expression of ALDP Is Altered in X‐linked Adrenoleukodystrophy

Watkins, Paul A.; Gould, Stephen J.; Smith, Madeleine L; Braiterman, Lelita T.; Wei, Heming; Kok, Fernando; Moser, Ann B.; Moser, Hugo W.; Smith, Kirby D.

doi:10.1111/j.1749-6632.1996.tb18693.x

Cited by 42 publications

(71 citation statements)

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“…X-linked adrenoleukodystrophy (X-ALD) 110362 and X-ALD 303617 are two human fibroblast cell lines from patients with ABCD1 gene mutations consistent with their clinical diagnosis of X-ALD (S. J. Steinberg, unpublished results), similar to the cell lines described in Ref. 23. The human Burkitt's lymphoma cell line, Daudi, does not express class I MHC molecules on the cell surface, because it lacks a functional ␤ 2 -microglobulin protein (24).…”

Section: Cell Linesmentioning

confidence: 59%

Bap31 Enhances the Endoplasmic Reticulum Export and Quality Control of Human Class I MHC Molecules

Ladasky

Boyle

Seth

et al. 2006

The Journal of Immunology

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The assembly of class I MHC molecules and their export from the endoplasmic reticulum (ER) is governed by chaperones and accessory proteins. We present evidence that the putative cargo receptor protein Bap31 participates in the transport and the quality control of human class I molecules. Transfection of the human adenocarcinoma cell line HeLa with yellow fluorescent protein-Bap31 chimeras increased surface levels of class I in a dose-dependent manner, by as much as 3.7-fold. The increase in surface class I resulted from an increase in the rate of export of newly synthesized class I molecules to the cell surface and from an increase in the stability of the exported molecules. We propose that Bap31 performs quality control on class I molecules in two distinct phases: first, by exporting peptide-loaded class I molecules to the ER/Golgi intermediate compartment, and second, by retrieving class I molecules that have lost peptides in the acidic post-ER environment. This function of Bap31 is conditional or redundant, because we find that Bap31 deficiency does not reduce surface class I levels. Overexpression of the Bap31 homolog, Bap29, decreases surface class levels in HeLa, indicating that it does not substitute for Bap31.

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Section: Cell Linesmentioning

confidence: 59%

Bap31 Enhances the Endoplasmic Reticulum Export and Quality Control of Human Class I MHC Molecules

Ladasky

Boyle

Seth

et al. 2006

The Journal of Immunology

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“…All TILLING and site-directed mutants expressed fulllength immunoreactive CTS at close to wild-type levels, in marked contrast to ALDP, in which about 70% of mutants, including several that correspond to the cts alleles generated in this study, do not produce immunoreactive protein at the peroxisomal membrane (Supplementary Table S1; Watkins et al, 1995;Feigenbaum et al, 1996;Kemp et al, 2001). Intriguingly, this implies that there are different mechanisms for sensing mutant peroxisomal membrane proteins in humans and plants and/or that such proteins with altered functionality have different fates in the cell.…”

Section: Cts Mis-sense Mutants Produce Stable Proteinmentioning

confidence: 99%

“…Several of the mutations generated in the CTS allelic series have equivalents in X-linked adrenoleukodystrophy patients (Supplementary Table S1; http:/www. x-ald.nl; Kemp et al, 2001).As mutations in ALDP have been shown to affect protein stability in many cases (Watkins et al, 1995;Feigenbaum et al, 1996;Kemp et al, 2001), we probed Western blots with proteins from 4-d-old seedlings with an antibody raised against the C-terminus of CTS (residues 1112-1337; Figure 1B). For previously published alleles, this analysis detected ped3-2 and ped3-4 mutant proteins only, which contain the single amino exchanges R1035W and S810N, respectively (Hayashi et al, 2002).…”

mentioning

confidence: 99%

Mutations in theArabidopsisPeroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

Dietrich

Schmuths

Lousa

et al. 2009

MBoC

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COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal ␤-oxidation.A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of conserved residues in the Walker A and B motifs in CTS nucleotide-binding domain (NBD) 1 resulted in a null phenotype but had little effect in NBD2, indicating that the NBDs are functionally distinct in vivo. Two alleles containing mutations in NBD1 outside the Walker motifs (E617K and C631Y) exhibited resistance to auxin precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) but were wild type in all other tests. The homology model predicted that the transmission interfaces are domain-swapped in CTS, and the differential effects of mutations in the conserved "EAA motif" of coupling helix 2 supported this prediction, consistent with distinct roles for each NBD. Our findings demonstrate that CTS functions can be separated by mutagenesis and the structural model provides a framework for interpretation of phenotypic data. INTRODUCTIONATP-binding cassette (ABC) transporters are ubiquitous, integral membrane proteins that mediate vectorial transport of a diverse range of molecules across membranes and consequently are involved in a wide variety of biological processes (Higgins, 1992;Rea, 2007). All ABC transporters share the same basic architecture, comprising two transmembrane domains (TMDs), each composed of several ␣-helices that are involved in substrate recognition and translocation across the lipid bilayer, and two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP, providing the driving force for transport. In prokaryotes, these domains are usually present on separate polypeptides, whereas in eukaryotes, fusion of a TMD and NBD module to form a "half transporter," or indeed fusion of all modules to form a "full transporter" is more common. The past decade has seen the determination of high-resolution crystal structures for several isolated NBDs and, more recently, complete ABC transporters (reviewed in .The NBDs characteristically contain several highly conserved features common to nucleotide hydrolases, including the Walker A motif (GxxGxGKS/T, where x is any amino acid), forming the P-loop, which binds to the ␣-and ␤-phosphates of nucleotides, and the Walker B motif (⌽⌽⌽⌽DE, where ⌽ is hydrophobic), thought to coordinate the Mg 2ϩ ion or polarize the attacking water molecule (Walker et al., 1982;Hung et al., 1998;Schneider and Hunke, 1998;Hopfner et al., 2000). ABC transporters additionally contain the signature motif (LSGGQ), which contacts the ␥-phosphate of ATP; the Q-loop (or "lid") containing a glutamine residue, which interacts with ␥-phosphate through a water molecule; and the swi...

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“…O diagnóstico é confirmado pelas altas concentrações plasmáticas de AGCML, principalmente os ácidos tetracosanóico (C24:0) e hexacosanóico (C26:0) e por alterações radiológicas típicas com grandes áreas simétricas de desmielinização parieto-occipital (24). A imunodetecção da proteína ALD por imunofluorescência indireta em fibroblastos ou leucócitos pode ser útil para identificação de pacientes heterozigotas, parentes de pacientes com ALD, especialmente nas famílias em que o defeito molecular não pode ser caracterizado (29,30).…”

Section: Adrenoleucodistrofia E Adrenoneuromielopatiaunclassified

Insuficiência Adrenal Primária de Causa Genética

Elias

Castro

2002

Arq Bras Endocrinol Metab

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Arq Bras Endocrinol Metab vol 46 nº 4 Agosto 2002 478 RESUMOA insuficiência adrenal primária pode resultar em uma situação de risco de vida, quando não tratada ou quando o paciente é submetido a situações de estresse. Desta maneira, o reconhecimento, diagnóstico e tratamento correto e precoce da insuficiência adrenal é de fundamental importância na prática clínica. Por outro lado, o avanço no conhecimento dos mecanismos moleculares das diferentes causas genéticas de insuficiência adrenal tem permitido melhor entendimento não só da fisiopatologia, mas também do desenvolvimento e fisiologia da glându-la adrenal. Esta revisão apresenta aspectos clínicos e moleculares de diferentes causas de insuficiência adrenal de origem genética. A GLÂNDULA ADRENAL PRODUZ esteróides que apresentam ações fisiológicas vitais. Assim, a insuficiência adrenal primária (IAP) pode resultar em uma situação de risco de vida, quando não tratada ou em situações de estresse. As diferentes causas de IAP podem ser agrupadas em: alterações do desenvolvimento da glândula, destruição da glândula e deficiência na síntese de cortisol (1). A prevalência das diferentes causas de IAP varia de acordo com a faixa etária. Na criança, a causa mais comum é a hiperplasia adrenal congênita, doença autossômica recessiva decorrente da deficiência de uma das cinco enzimas envolvidas na síntese de cortisol. Na vida adulta, as causas mais comuns incluem a adrenalite autoimune e, em nosso meio, também a tuberculose e a paracoccidioidomicose. Neste texto abordaremos as causas genéticas, excetuando-se a hiperplasia adrenal congênita que está contemplada em outra revisão desta mesma edição.

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Expression of ALDP Is Altered in X‐linked Adrenoleukodystrophy

Cited by 42 publications

References 0 publications

Bap31 Enhances the Endoplasmic Reticulum Export and Quality Control of Human Class I MHC Molecules

Bap31 Enhances the Endoplasmic Reticulum Export and Quality Control of Human Class I MHC Molecules

Mutations in theArabidopsisPeroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

Insuficiência Adrenal Primária de Causa Genética

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