G. Grobner | Umeå University (original) (raw)

Papers by G. Grobner

Journal of Biological Chemistry, 2010

In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associ... more In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

The FASEB Journal, 2009

Using a noninvasive, solid-state magicangle spinning nuclear magnetic resonance (MAS NMR) approac... more Using a noninvasive, solid-state magicangle spinning nuclear magnetic resonance (MAS NMR) approach, we track ex vivo the behavior of individual membrane components in isolated, active mitochondria (model system: potato tubers) during physiological processes. The individual phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) membrane constituents were identified as distinct lines by applying MAS 31 P NMR on extracted lipid membranes. However, the CL NMR signal appeared to be very broad in functional mitochondria, indicating a tight complex formation with membrane protein. Calcium stress induced severe membrane degradation without recovery of a single CL NMR resonance. This suggests that calcium overload destroys the outer mitochondrial membrane and does not modify strongly the CL protein complexes in the inner membrane; a conclusion confirmed by respiratory controls.

Proceedings of the National Academy of Sciences, 2009

The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically o... more The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn 2؉ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a nonnative Zn 2؉ ion with M affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn 2؉ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features. functional evolution ͉ protein disease ͉ protein misfolding

Current Opinion in Colloid & Interface Science, 2006

Physico-chemical properties of lipid bilayers play an important role in many biomembrane processe... more Physico-chemical properties of lipid bilayers play an important role in many biomembrane processes, ranging from membrane trafficking and membrane signaling, over membrane protein folding and peptide induced membrane fusion to even aggregation. In recent years much interest has been devoted to the occurring interactions between various lipid components and membrane-associated peptides and membrane proteins. NMR methods for such studies have been successfully utilized and are now routinely employed in these areas. D

In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associ... more In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

Biogeochemistry, 2012

... AG Vincent (&) Á M. Jansson Department of Ecology and Environmental Sciences, Umeå Univer... more ... AG Vincent (&) Á M. Jansson Department of Ecology and Environmental Sciences, Umeå University, 901 87 Umeå, Sweden e-mail: andrea.vincent@emg.umu.se J. Schleucher Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden ...

Journal of Biological Chemistry, 2010

In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associ... more In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

The FASEB Journal, 2009

Using a noninvasive, solid-state magicangle spinning nuclear magnetic resonance (MAS NMR) approac... more Using a noninvasive, solid-state magicangle spinning nuclear magnetic resonance (MAS NMR) approach, we track ex vivo the behavior of individual membrane components in isolated, active mitochondria (model system: potato tubers) during physiological processes. The individual phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) membrane constituents were identified as distinct lines by applying MAS 31 P NMR on extracted lipid membranes. However, the CL NMR signal appeared to be very broad in functional mitochondria, indicating a tight complex formation with membrane protein. Calcium stress induced severe membrane degradation without recovery of a single CL NMR resonance. This suggests that calcium overload destroys the outer mitochondrial membrane and does not modify strongly the CL protein complexes in the inner membrane; a conclusion confirmed by respiratory controls.

Proceedings of the National Academy of Sciences, 2009

The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically o... more The structural integrity of the ubiquitous enzyme superoxide dismutase (SOD1) relies critically on the correct coordination of Cu and Zn. Loss of these cofactors not only promotes SOD1 aggregation in vitro but also seems to be a key prerequisite for pathogenic misfolding in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We examine here the consequences of Zn 2؉ loss by selectively removing the Zn site, which has been implicated as the main modulator of SOD1 stability and disease competence. After Zn-site removal, the remaining Cu ligands can coordinate a nonnative Zn 2؉ ion with M affinity in the denatured state, and then retain this ion throughout the folding reaction. Without the restriction of a metallated Zn site, however, the Cu ligands fail to correctly coordinate the nonnative Zn 2؉ ion: Trapping of a water molecule causes H48 to change rotamer and swing outwards. The misligation is sterically incompatible with the native structure. As a consequence, SOD1 unfolds locally and interacts with neighboring molecules in the crystal lattice. The findings point to a critical role for the native Zn site in controlling SOD1 misfolding, and show that even subtle changes of the metal-loading sequence can render the wild-type protein the same structural properties as ALS-provoking mutations. This frustrated character of the SOD1 molecule seems to arise from a compromise between optimization of functional and structural features. functional evolution ͉ protein disease ͉ protein misfolding

Current Opinion in Colloid & Interface Science, 2006

Physico-chemical properties of lipid bilayers play an important role in many biomembrane processe... more Physico-chemical properties of lipid bilayers play an important role in many biomembrane processes, ranging from membrane trafficking and membrane signaling, over membrane protein folding and peptide induced membrane fusion to even aggregation. In recent years much interest has been devoted to the occurring interactions between various lipid components and membrane-associated peptides and membrane proteins. NMR methods for such studies have been successfully utilized and are now routinely employed in these areas. D

In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associ... more In good accord with the protein aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apoSOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apoSOD1 is the elimination or introduction of a single charge, i.e. D76V/Y, D101N, and N139D/K. The thermodynamic stability and folding behavior of these mutants are indistinguishable from the wild-type control. Moreover, D101N is an outlier in the plot of stability loss versus patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

Biogeochemistry, 2012

... AG Vincent (&) Á M. Jansson Department of Ecology and Environmental Sciences, Umeå Univer... more ... AG Vincent (&) Á M. Jansson Department of Ecology and Environmental Sciences, Umeå University, 901 87 Umeå, Sweden e-mail: andrea.vincent@emg.umu.se J. Schleucher Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden ...