Characterization and functional analysis of the nucleotide binding fold in human peroxisomal ATP binding cassette transporters
Open accessAbstract
The 70‐kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. Mutations in the ALD gene encoding ALDP result in the X‐linked neurodegenerative disorder adrenoleukodystrophy. Plausible models exist to show a role for ATP hydrolysis in peroxisomal ABC transporter functions. Here, we describe the first measurements of the rate of ATP binding and hydrolysis by purified nucleotide binding fold (NBF) fusion proteins of PMP70 and ALDP. Both proteins act as an ATP specific binding subunit releasing ADP after ATP hydrolysis; they did not exhibit GTPase activity. Mutations in conserved residues of the nucleotidases (PMP70: G478R, S572I; ALDP: G512S, S606L) altered ATPase activity. Furthermore, our results indicate that these mutations do not influence homodimerization or heterodimerization of ALDP or PMP70. The study provides evidence that peroxisomal ABC transporters utilize ATP to become a functional transporter.
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The pathogenic variant p.Ser606Leu affects ATP-binding capacity and results in deficient VLCFA beta-oxidation.
“Studies using experimental cell lines showed that the pathogenic variant affects ATP-binding capacity (Database Refs 194 and 244) [22,23], resulting in deficient VLCFA beta-oxidation (Database Ref 261) [24].”
From Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy (2022) · cites this paper as [23]
For two missense mutations in functional regions of the ALDP ATP-binding domain, S606L resulted in decreased ATP-binding capacity and G512S resulted in reduced ATPase activity.
“For two missense mutations located in functional regions of the ATP-binding domain it was demonstrated that the mutations resulted in either decreased ATPbinding capacity (S606L) or reduced ATPase activity (G512S) [Roerig et al., 2001].”
From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Roerig et al., 2001
The nucleotide-binding fold of ALDP acts as an ATP-binding subunit with ATPase activity.
“It was demonstrated recently that the nucleotide-binding fold of ALDP acts as an ATP-binding subunit with ATPase activity [Roerig et al., 2001].”
From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Roerig et al., 2001
Cites
Primary Structure of Human PMP69, a Putative Peroxisomal ABC-Transporter
Holzinger, A., Kammerer, S., & Roscher, A. A. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7102 · Cited by 91 · see citing works
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Kemp, S., Pujol, A., Waterham, H. R., van Geel, B. M., Boehm, C. D., Raymond, G. V., Cutting, G. R., Wanders, R. J. A., & Moser, H. W. (2001) · Human Mutation · doi:10.1002/humu.1227 · Cited by 332 · see citing works
Peroxisomal ABC transporters: Structure, function and role in disease
Morita, M., & Imanaka, T. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.02.009 · Cited by 183 · see citing works
Biochemical aspects of X-linked adrenoleukodystrophy
Kemp, S., & Wanders, R. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2010.00391.x · Cited by 116 · see citing works
Kemp, S., & Wanders, R. J. A. (2007) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2006.10.001 · Cited by 82 · see citing works
Torres, S. E., Gallagher, C. M., Plate, L., Gupta, M., Liem, C. R., Guo, X., Tian, R., Stroud, R. M., Kampmann, M., Weissman, J. S., et al. (2019) · eLife · doi:10.7554/elife.46595 · Cited by 76 · see citing works
Peroxisomal ABC Transporters: An Update
Tawbeh, A., Gondcaille, C., Trompier, D., & Savary, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116093 · Cited by 68 · see citing works
Mallack, E. J., Gao, K., Engelen, M., & Kemp, S. (2022) · Cells · doi:10.3390/cells11020283 · Cited by 60 · see citing works
“Studies using experimental cell lines showed that the pathogenic variant affects ATP-binding capacity (Database Refs 194 and 244) [22,23], resulting in deficient VLCFA beta-oxidation (Database Ref 261) [24].”
BackgroundFunctional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis
Gärtner, J., Dehmel, T., Klusmann, A., & Roerig, P. (2002) · Endocrine Research · doi:10.1081/erc-120016999 · Cited by 15 · see citing works
Self-citation
- Authors
- Roerig, P., Mayerhofer, P., Holzinger, A., & Gärtner, J.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Gärtner, Jutta
- ORCID
- Gärtner, Jutta
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2001-03-07
- Volume
- 492
- Issue
- 1-2
- Pages
- 66-72
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W1982619578
- Cited by
- 40
- References
- 1
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2017: 1 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- GRO (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- PMP70, nucleotide binding fold, ATP hydrolysis, ATP binding, GTPase activity, protein dimerization, adrenoleukodystrophy
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adenosine Triphosphatases, Adenosine Triphosphate, Amino Acid Sequence, Animals, Escherichia coli, Humans, Membrane Proteins, Molecular Sequence Data, Rabbits, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, ATP-Binding Cassette Transporters, GTP Phosphohydrolases, Peroxisomes, Amino Acid Motifs
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