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ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP
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Abstract
The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 Å and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.
Title: ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP
Description:
Abstract
The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human.
Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation.
Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states.
Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 Å and the rearrangement of the transmembrane domains.
Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size.
Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release.
The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.
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ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP
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Abstract
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