Thermodynamic Interrogation of a Folding Disease. Mutant Mapping of Position 107 in Human Carbonic Anhydrase II Linked to Marble Brain Disease

Almstedt, Karin; Mårtensson, Lars-Göran; Carlsson, Uno; Hammarström, Per

doi:10.1021/bi701720p

Cited by 7 publications

(17 citation statements)

References 43 publications

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“…To determine the stabilization capability of the different inhibitors at pH 7.5, we measured the stability, by the change in intrinsic Trp fluorescence, toward both GuHCl denaturation at 4°C and thermal denaturation. Due to the high number of Trps in HCA II, and the even distribution thereof, this is a sensitive method to monitor the global unfolding of the protein (26 (27,28), but furthermore severely destabilized mutants of HCA II (such as H107Y) also populate a more native-like intermediate abbreviated molten globule light state (10,11). All unfolding curves both in the presence and in the absence of inhibitor showed similar unfolding trajectories (Figure 2), but with higher midpoints of thermal denaturation (T m ) and midpoint concentrations of GuHCl denaturation (C m ) compared to the corresponding values of the unliganded mutant.…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease

et al. 2009

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Carbonic anhydrase II deficiency syndrome or Marble brain disease (MBD) is caused by autosomal recessive mutations in the human carbonic anhydrase II (HCA II) gene. Here we report a small-molecule stabilization study of the exceptionally destabilized HCA II mutant H107Y employing inhibitors based on p-aminobenzoylsulfonamide compounds and 1,3,4-thiadiazolylsulfonamides as well as amino acid activators. Protein stability assays showed a significant stabilization by the aromatic sulfonamide inhibitors when present at 10 microM concentration, providing shifts of the midpoint of thermal denaturation between 10 degrees C and 16 degrees C and increasing the free energies of denaturation 0.5-3.0 kcal/mol as deduced from GuHCl denaturation. This study could be used as a starting point for the design of small-molecule folding modulators and possibly autoactivatable molecules for suppression of misfolding of destabilized HCA II mutants.

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Section: Resultsmentioning

confidence: 99%

Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease

et al. 2009

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“…The melting temperature, T m of wild type HCA II, obtained from the midpoint of differential calorimetry curves, is

\sim 58^{normalo}

C while it is estimated to become catalytically inactive at around

60^{\circ}

C . However, perturbation of this stable fold by a single‐point mutation at the residue His‐107 of the wild type protein has been shown to be highly destabilizing under physiological conditions . In the present article, we focus on one such single‐point mutant His‐107‐Tyr of HCA II to explore key thermal unfolding intermediate(s) using classical molecular dynamics simulation.…”

Section: Introductionmentioning

confidence: 99%

“…The mutant His‐107‐Tyr of HCA II is reported to be linked to the misfolding disease, carbonic anhydrase II deficiency syndrome (CADS) or marble brain syndrome (MBS) . The native state stability of the mutant is found to be decreased by

9.2 k c a l m o l^{- 1}

compared to the wild type enzyme and its midpoint of denaturation ( T m ) decreases to

22^{normalo}

C.…”

Section: Introductionmentioning

confidence: 99%

“…(a)] and include both α and

3_{10}

‐helices. In the wild type HCA II, His‐107 is known to be a part of the hydrogen bonded network that starts from His‐119 at the active site and ends at Trp‐209 via Glu‐117, Tyr‐194, Ser‐29, and Ser‐197 . This network holds the large aromatic moiety of Trp‐209 residue on the β ‐core with the N‐terminal invariant residue Ser‐29 .…”

Section: Introductionmentioning

confidence: 99%

“…In the GuHCl‐induced denaturation of the mutant His‐107‐Tyr at

4^{o}

C, an early intermediate, molten globule light (MGL) state is detected preceding the classical MG state. Both the intermediates are prone to aggregation and enzymatically inactive.…”

Section: Introductionmentioning

confidence: 99%

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Identification of putative unfolding intermediates of the mutant His‐107‐tyr of human carbonic anhydrase II in a multidimensional property space

Halder

Taraphder

2016

Proteins

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In this article, we develop an extensive search procedure of the multi-dimensional folding energy landscape of a protein. Our aim is to identify different classes of structures that have different aggregation propensities and catalytic activity. Following earlier studies by Daggett et al. [Jong, D. D.; Riley, R.: Alonso, D.O.: Dagett, V. J. Mol. Biol. 2002, 319, 229], a series of high temperature all-atom classical molecular simulation studies has been carried out to derive a multi-dimensional property space. Dynamical changes in these properties are then monitored by projecting them along a one-dimensional reaction coordinate, dmean . We have focused on the application of this method to partition a wide array of conformations of wild type human carbonic anhydrase II (HCA II) and its unstable mutant His-107-Tyr along dmean by sampling a 35-dimensional property space. The resultant partitioning not only reveals the distribution of conformations corresponding to stable structures of HCA II and its mutant, but also allows the monitoring of several partially unfolded and less stable conformations of the mutant. We have investigated the population of these conformations at different stages of unfolding and collected separate sets of structures that are widely separated in the property space. The dynamical diversity of these sets are examined in terms of the loading of their respective first principal component. The partially unfolded structures thus collected are qualitatively mapped on to the experimentally postulated light molten globule (MGL) and molten globule (MG) intermediates with distinct aggregation propensities and catalytic activities. Proteins 2016; 84:726-743. © 2016 Wiley Periodicals, Inc.

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Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?

Ittisoponpisan

Islam

Khanna

et al. 2019

Journal of Molecular Biology

409

334

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Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of the 2134 neutral variants are structurally damaging. Importantly, similar results are obtained when 1052 structures predicted using Phyre2 algorithm were used, even when the model shares low (< 40%) sequence identity to the template. Thus, structure-based analysis of the effects of missense variants can be effectively applied to homology models. Our in-house pipeline, Missense3D, for structurally assessing missense variants was made available at http://www.sbg.bio.ic.ac.uk/~missense3d

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Thermodynamic Interrogation of a Folding Disease. Mutant Mapping of Position 107 in Human Carbonic Anhydrase II Linked to Marble Brain Disease

Cited by 7 publications

References 43 publications

Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease

Small-Molecule Suppression of Misfolding of Mutated Human Carbonic Anhydrase II Linked to Marble Brain Disease

Identification of putative unfolding intermediates of the mutant His‐107‐tyr of human carbonic anhydrase II in a multidimensional property space

Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?

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