A Disorder to Order Transition Accompanies Catalysis in Retinaldehyde Dehydrogenase Type II

Bordelon, Tee; Montegudo, Sarah K.; Pakhomova, Svetlana; Oldham, Michael L.; Newcomer, Marcia E.

doi:10.1074/jbc.m406139200

Cited by 20 publications

(24 citation statements)

References 31 publications

(32 reference statements)

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“…Lamb and Newcomer have reported these residues missing in the electron density maps of cofactor-bound retinal dehydrogenase type II (RalDH2), which shares about 67% sequence identity with ALDH2 (26,27). What is unique to ALDH2*2 is the complete loss of both the loop and the ␣G helix in the electron density maps.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the Coenzyme Binding Site and Dimer Interface Revealed in the Crystal Structure of Mitochondrial Aldehyde Dehydrogenase “Asian” Variant

Larson

Weiner

Hurley

2005

Journal of Biological Chemistry

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Mitochondrial aldehyde dehydrogenase (ALDH2) is the major enzyme that oxidizes ethanol-derived acetaldehyde. A nearly inactive form of the enzyme, ALDH2*2, is found in about 40% of the East Asian population. This variant enzyme is defined by a glutamate to lysine substitution at residue 487 located within the oligomerization domain. ALDH2*2 has an increased K m for its coenzyme, NAD ؉ , and a decreased k cat , which lead to low activity in vivo. Here we report the 2.1 Å crystal structure of ALDH2*2. The structure shows a large disordered region located at the dimer interface that includes much of the coenzyme binding cleft and a loop of residues that form the base of the active site. As a consequence of these structural changes, the variant enzyme exhibits rigid body rotations of its catalytic and coenzyme-binding domains relative to the oligomerization domain. These structural perturbations are the direct result of the inability of lysine 487 to form important stabilizing hydrogen bonds with arginines 264 and 475. Thus, the elevated K m for coenzyme exhibited by this variant probably reflects the energetic penalty for reestablishing this site for productive coenzyme binding, whereas the structural alterations near the active site are consistent with the lowered V max .

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Section: Discussionmentioning

confidence: 99%

Disruption of the Coenzyme Binding Site and Dimer Interface Revealed in the Crystal Structure of Mitochondrial Aldehyde Dehydrogenase “Asian” Variant

Larson

Weiner

Hurley

2005

Journal of Biological Chemistry

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“…34 to become ordered, and this constitutes the basis for its substrate specificity. 49 The YcdW ALDH and the TtP5CDh also have the arginine equivalent to E248 of PaBADH, but its side chain is outside the cation binding cavity, and still their structures show no disorder. The electron density map of these crystals indicates that it is likely that they do have a cation bound inside this cavity.…”

Section: Binding Of K + Ionsmentioning

confidence: 99%

The Crystal Structure of A Ternary Complex of Betaine Aldehyde Dehydrogenase from Pseudomonas aeruginosa Provides New Insight into the Reaction Mechanism and Shows A Novel Binding Mode of the 2′-Phosphate of NADP+ and A Novel Cation Binding Site

González‐Segura

Rudino‐Pinera

Muñoz‐Clares

et al. 2009

Journal of Molecular Biology

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“…1) IDPs have no unique three-dimensional structure in an isolated state but can fold upon binding to their interaction partners [1], [4], [13]–[18]. 2) Conformational changes upon binding in proteins with unstructured regions are much larger than those in structured proteins [1].…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Disorder in Protein Interactions: Insights From a Comprehensive Structural Analysis

et al. 2009

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We perform a large-scale study of intrinsically disordered regions in proteins and protein complexes using a non-redundant set of hundreds of different protein complexes. In accordance with the conventional view that folding and binding are coupled, in many of our cases the disorder-to-order transition occurs upon complex formation and can be localized to binding interfaces. Moreover, analysis of disorder in protein complexes depicts a significant fraction of intrinsically disordered regions, with up to one third of all residues being disordered. We find that the disorder in homodimers, especially in symmetrical homodimers, is significantly higher than in heterodimers and offer an explanation for this interesting phenomenon. We argue that the mechanisms of regulation of binding specificity through disordered regions in complexes can be as common as for unbound monomeric proteins. The fascinating diversity of roles of disordered regions in various biological processes and protein oligomeric forms shown in our study may be a subject of future endeavors in this area.

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A Disorder to Order Transition Accompanies Catalysis in Retinaldehyde Dehydrogenase Type II

Cited by 20 publications

References 31 publications

Disruption of the Coenzyme Binding Site and Dimer Interface Revealed in the Crystal Structure of Mitochondrial Aldehyde Dehydrogenase “Asian” Variant

Disruption of the Coenzyme Binding Site and Dimer Interface Revealed in the Crystal Structure of Mitochondrial Aldehyde Dehydrogenase “Asian” Variant

The Crystal Structure of A Ternary Complex of Betaine Aldehyde Dehydrogenase from Pseudomonas aeruginosa Provides New Insight into the Reaction Mechanism and Shows A Novel Binding Mode of the 2′-Phosphate of NADP+ and A Novel Cation Binding Site

Intrinsic Disorder in Protein Interactions: Insights From a Comprehensive Structural Analysis

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