Local Structural Stability of the Acyl-Coenzyme A Binding Protein by ESR Spectroscopy

Hung, Chien‐Lun; Lee, Su Wei; Chiang, Yun‐Wei

doi:10.1007/s00723-022-01476-w

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…Second, WSME-model-based analysis of bovine ACBP (both apo and holo forms) predicts a similar flexibility in H1, and a conformational-selection-like ligand binding mechanism . Third, electron spin resonance (ESR) spectroscopy of bovine ACBP highlights a distinct increase in H1–H4 interface stability on ligand binding, apart from the stabilization of binding site residues in H2 and H3 . Finally, humans harbor an N-terminal truncated isoform of ACBP, hACBP D1, that lacks the entire secondary structure element H1 .…”

Section: Discussionmentioning

confidence: 99%

“…26 Third, electron spin resonance (ESR) spectroscopy of bovine ACBP highlights a distinct increase in H1−H4 interface stability on ligand binding, apart from the stabilization of binding site residues in H2 and H3. 59 Finally, humans harbor an N-terminal truncated isoform of ACBP, hACBP D1, that lacks the entire secondary structure element H1. 60 This therefore suggests that the structure formed from helices H2− H3−H4 can act as an independent folding unit.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in Paralogous Plasmodium Acyl-CoA Binding Proteins

Dani,

Pawloski,

Chaurasiya

et al. 2023

Biochemistry

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Paralogous proteins confer enhanced fitness to organisms via complex sequence−conformation codes that shape functional divergence, specialization, or promiscuity. Here, we dissect the underlying mechanism of promiscuous binding versus partial subfunctionalization in paralogues by studying structurally identical acyl-CoA binding proteins (ACBPs) from Plasmodium falciparum that serve as promising drug targets due to their high expression during the protozoan proliferative phase. Combining spectroscopic measurements, solution NMR, SPR, and simulations on two of the paralogues, A16 and A749, we show that minor sequence differences shape nearly every local and global conformational feature. A749 displays a broader and heterogeneous native ensemble, weaker thermodynamic coupling and cooperativity, enhanced fluctuations, and a larger binding pocket volume compared to A16. Site-specific tryptophan probes signal a graded reduction in the sampling of substates in the holo form, which is particularly apparent in A749. The paralogues exhibit a spectrum of binding affinities to different acyl-CoAs with A749, the more promiscuous and hence the likely ancestor, binding 1000fold stronger to lauroyl-CoA under physiological conditions. We thus demonstrate how minor sequence changes modulate the extent of long-range interactions and dynamics, effectively contributing to the molecular evolution of contrasting functional repertoires in paralogues.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in Paralogous Plasmodium Acyl-CoA Binding Proteins

Dani,

Pawloski,

Chaurasiya

et al. 2023

Biochemistry

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Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in ParalogousPlasmodiumAcyl-CoA Binding Proteins

Dani,

Pawloski,

Chaurasiya

et al. 2023

Preprint

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Paralogous proteins confer enhanced fitness to organisms via complex sequence-conformation codes that shape functional divergence, specialization, or promiscuity. Here, we resolve the underlying mechanism of promiscuous binding versus partial sub-functionalization in paralogs by studying structurally-identical Acyl-CoA Binding Proteins (ACBPs) from Plasmodium falciparum that serve as promising drug targets due to their high expression during the protozoan proliferative phase. Combining spectroscopic measurements, solution NMR, SPR and simulations on two of the paralogs, A16 and A749, we show that minor sequence differences shape nearly every local and global conformational feature. A749 displays a broader and heterogeneous native ensemble, weaker thermodynamic coupling and cooperativity, enhanced fluctuations, and a larger binding-pocket volume, compared to A16. Site-specific tryptophan probes signal a graded reduction in the sampling of substates in the holo form, which is particularly more apparent in A749, hinting at conformational-selection-like mechanism of binding. The paralogs exhibit a spectrum of binding affinities to different acyl-CoAs with A749, the more promiscuous and hence the likely ancestor, binding 1000-fold stronger to Lauroyl-CoA under physiological conditions. We thus demonstrate how minor sequence changes modulate the extent of long-range interactions and dynamics, effectively contributing to the molecular evolution of contrasting functional repertoires in paralogs.

show abstract

Local Structural Stability of the Acyl-Coenzyme A Binding Protein by ESR Spectroscopy

Cited by 2 publications

References 27 publications

Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in Paralogous Plasmodium Acyl-CoA Binding Proteins

Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in Paralogous Plasmodium Acyl-CoA Binding Proteins

Conformational Tuning Shapes the Balance between Functional Promiscuity and Specialization in ParalogousPlasmodiumAcyl-CoA Binding Proteins

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