Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain Acyl-CoA Dehydrogenase
Abstract
Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Unlike the other ACADs, which are soluble homotetramers, VLCAD is a homodimer associated with the mitochondrial membrane. VLCAD also possesses an additional 180 residues in the C terminus that are not present in the other ACADs. We have determined the crystal structure of VLCAD complexed with myristoyl-CoA, obtained by co-crystallization, to 1.91-{angstrom} resolution. The overall fold of the N-terminal {approx}400 residues of VLCAD is similar to that of the soluble ACADs including medium-chain acyl-CoA dehydrogenase (MCAD). The novel C-terminal domain forms an {alpha}-helical bundle that is positioned perpendicular to the two N-terminal helical domains. The fatty acyl moiety of the bound substrate/product is deeply imbedded inside the protein; however, the adenosine pyrophosphate portion of the C14-CoA ligand is disordered because of partial hydrolysis of the thioester bond and high mobility of the CoA moiety. The location of Glu-422 with respect to the C2-C3 of the bound ligand and FAD confirms Glu-422 to be the catalytic base. In MCAD, Gln-95 and Glu-99 form the base of the substrate binding cavity. In VLCAD, these residues are glycines (Gly-175 and Gly-178), allowing the binding channel to extend for anmore »
- Authors:
-
- Pitt
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1006662
- Resource Type:
- Journal Article
- Journal Name:
- J. Biol. Chem.
- Additional Journal Information:
- Journal Volume: 283; Journal Issue: (14) ; 04, 2008; Journal ID: ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; ACYL RADICALS; ADENOSINE; CELL MEMBRANES; CRYSTAL STRUCTURE; DEFECTS; GENOTYPE; HYDROLYSIS; LIGANDS; MITOCHONDRIA; MOBILITY; OXIDOREDUCTASES; PHENOTYPE; PYROPHOSPHATES; RESIDUES; RESOLUTION; SPECIFICITY; SUBSTRATES
Citation Formats
McAndrew, Ryan P, Wang, Yudong, Mohsen, Al-Walid, He, Miao, Vockley, Jerry, Kim, Jung-Ja P, and MCW). Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain Acyl-CoA Dehydrogenase. United States: N. p., 2008.
Web. doi:10.1074/jbc.M709135200.
McAndrew, Ryan P, Wang, Yudong, Mohsen, Al-Walid, He, Miao, Vockley, Jerry, Kim, Jung-Ja P, & MCW). Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain Acyl-CoA Dehydrogenase. United States. https://doi.org/10.1074/jbc.M709135200
McAndrew, Ryan P, Wang, Yudong, Mohsen, Al-Walid, He, Miao, Vockley, Jerry, Kim, Jung-Ja P, and MCW). 2008.
"Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain Acyl-CoA Dehydrogenase". United States. https://doi.org/10.1074/jbc.M709135200.
@article{osti_1006662,
title = {Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain Acyl-CoA Dehydrogenase},
author = {McAndrew, Ryan P and Wang, Yudong and Mohsen, Al-Walid and He, Miao and Vockley, Jerry and Kim, Jung-Ja P and MCW)},
abstractNote = {Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Unlike the other ACADs, which are soluble homotetramers, VLCAD is a homodimer associated with the mitochondrial membrane. VLCAD also possesses an additional 180 residues in the C terminus that are not present in the other ACADs. We have determined the crystal structure of VLCAD complexed with myristoyl-CoA, obtained by co-crystallization, to 1.91-{angstrom} resolution. The overall fold of the N-terminal {approx}400 residues of VLCAD is similar to that of the soluble ACADs including medium-chain acyl-CoA dehydrogenase (MCAD). The novel C-terminal domain forms an {alpha}-helical bundle that is positioned perpendicular to the two N-terminal helical domains. The fatty acyl moiety of the bound substrate/product is deeply imbedded inside the protein; however, the adenosine pyrophosphate portion of the C14-CoA ligand is disordered because of partial hydrolysis of the thioester bond and high mobility of the CoA moiety. The location of Glu-422 with respect to the C2-C3 of the bound ligand and FAD confirms Glu-422 to be the catalytic base. In MCAD, Gln-95 and Glu-99 form the base of the substrate binding cavity. In VLCAD, these residues are glycines (Gly-175 and Gly-178), allowing the binding channel to extend for an additional 12{angstrom} and permitting substrate acyl chain lengths as long as 24 carbons to bind. VLCAD deficiency is among the more common defects of mitochondrial {beta}-oxidation and, if left undiagnosed, can be fatal. This structure allows us to gain insight into how a variant VLCAD genotype results in a clinical phenotype.},
doi = {10.1074/jbc.M709135200},
url = {https://www.osti.gov/biblio/1006662},
journal = {J. Biol. Chem.},
issn = {0021-9258},
number = (14) ; 04, 2008,
volume = 283,
place = {United States},
year = {Tue Aug 26 00:00:00 EDT 2008},
month = {Tue Aug 26 00:00:00 EDT 2008}
}