Structure of Mitochondrial Aldehyde Dehydrogenase

The enzyme is a tetramer (below) comprised of four identical 55 kD subunits (500 amino acids per subunit). This structure has been solved to 1.9 Å as a binary complex with NADH, to 1.4 Å as a binary complex with NAD⁺ and to 2.25 Å as the apo-enzyme.

Each subunit (below) is comprised of three domains; two alpha/beta domains, and a smaller third domain that is involved in subunit interactions, both in the dimer and in the tetramer.

This is more easily seen in a different view of the tetramer (below) where you can see the three beta-strands from the smaller oligomerization domain interacting with both its neighbor in the dimer and with its neighbor in the tetramer (the cofactor molecules are colored purple in this representation and the position of Glu 487 is shown in cyan).

Glu487 is mutated to Lys in the naturally occuring variant, ALDH2*2, found in about 50% of the Asian population.  We recently published the structure of the apo-enzyme form of the ALDH2*2 enzyme to 2.1 Å resolution.  The remarkable aspect of the structure of ALDH2*2 is that the substitution of Glu487 by Lys leads to the disordering of a large section of the protein structure that includes most of the coenzyme binding site.  Thus, the low affinity for coenzyme and low activity associated with this form of ALDH2 is primarily due to the structural instability brought about by the introduction of another positively charged residue in this part of the protein structure.

References:

C. Steinmetz, P. Xie, H. Weiner, and T.D. Hurley (1997) Structure of mitochondrial aldehyde dehydrogenase. Structure 5, 701-711.

Hurley, T.D., Steinmetz, C.G., and Weiner, H. (1999) Three-dimensional structure of mitochondrial aldehyde dehydrogenase: mechanistic implications. Adv. Exptl. Med. & Biol. 463, 15-25.

Ni , L., Zhou, J., Hurley, T.D., and Weiner, H. (1999) Human Liver Mitochondrial Aldehyde dehydrogenase: Three-dimensional structure and restoration of solubility and activity to chimeric forms. Protein Science 8, 2784-2790.

Wei, B., Ni, L., Hurley, T.D. and Weiner, H. (2000) Cooperativity in NAD⁺ binding induced by mutations of Arginine 475 located at the subunit interface in human liver mitochondrial Class 2 aldehyde dehydrogenase. Biochemistry 39:5295-5302.

Hammen, P.K., Allali-Hassani, A., Hallenga, K., Hurley, T.D., and Weiner, H. (2002) Multiple conformations of NAD⁺ and NADH when bound to human cytosolic and mitochondrial aldehyde dehydrogenase. Biochemistry 41:7156-7168.

Perez-Miller, S. and Hurley, T.D. (2003) Coenzyme isomerization is integral to catalysis in aldehyde dehydrogenase. Biochemistry 42:7100-7109.

Ho, K.K., Allali-Hassani, A., Hurley,T.D., and Weiner, H. (2005) Differential effects of Mg²⁺ ions on the individual kinetic steps of human cytosolic and mitochondrial aldehyde dehydrogenases. Biochemistry 44:8022-8029.

 

Larson, H., Weiner, H., and Hurley, T.D. (2005) Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase “asian” variant. J. Biol. Chem. 280:30550-30556.

Larson, H., Zhou, J., Chen, Z., Stamler, J.S., Weiner, H. and Hurley, T.D. (2007) Structural and Functional Consequences of Coenzyme Binding to the Inactive Asian Variant of Mitochondrial Aldehyde Dehydrogenase: Roles of Residues 475 and 487. J. Biol. Chem. (in press).