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Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.

Castillo V, Ventura S - PLoS Comput. Biol. (2009)

Bottom Line: The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell.Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates.It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.

View Article: PubMed Central - PubMed

Affiliation: Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.

ABSTRACT
Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.

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Related in: MedlinePlus

Aggregation and interaction regions in human transthyretin.In all panels, transthyretin (TTR) aggregation-prone residues at less and more than 3 Å from interaction sites are shown in red and green, respectively. Interface residues not included in aggregation-prone regions are shown in dark blue. Rest of residues are shown in light blue. A) The predicted interaction surface of a TTR monomer is used for calculation. B) The interface in the native tetrameric structure of TTR is used for calculation (PDB ID:1TTA). C) Dimer of TTR. D) TTR native tetrameric structure. The first dimer is twisted 90° relative to C, the second one is shown in yellow.
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pcbi-1000476-g003: Aggregation and interaction regions in human transthyretin.In all panels, transthyretin (TTR) aggregation-prone residues at less and more than 3 Å from interaction sites are shown in red and green, respectively. Interface residues not included in aggregation-prone regions are shown in dark blue. Rest of residues are shown in light blue. A) The predicted interaction surface of a TTR monomer is used for calculation. B) The interface in the native tetrameric structure of TTR is used for calculation (PDB ID:1TTA). C) Dimer of TTR. D) TTR native tetrameric structure. The first dimer is twisted 90° relative to C, the second one is shown in yellow.

Mentions: A single interaction patch is predicted for the TTR monomer (Figure 3A). It involves 19 residues located in the A β-strand (L17, A19), in the loop between the A and B β-strands (V20–S23), in the α-helix (L82), in the loop between the helix and the F β-strand (S85-F87), in the F β-strand (E92), in the G and H β-strands, and in the loop between the G and H β-strands (L110, S112-T118). TTR is a dimer of dimers. In the dimers formed by the A and B or the C and D chains, the predicted clusters are contiguous, forming a large and continuous interaction patch. Of the residues in aggregation-prone regions in TTR, 41% are within 3 Å of predicted interaction sites (Table 1). With the exception of the I26-R34 fragment, all the regions with high aggregation propensity are located close to the predicted interface, and 30% of the residues in these segments overlap with predicted interaction sites. Residues 17, 19, 92, 110, 112, and the stretch 115–118 are predicted to be important both for aggregation and interaction events.


Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.

Castillo V, Ventura S - PLoS Comput. Biol. (2009)

Aggregation and interaction regions in human transthyretin.In all panels, transthyretin (TTR) aggregation-prone residues at less and more than 3 Å from interaction sites are shown in red and green, respectively. Interface residues not included in aggregation-prone regions are shown in dark blue. Rest of residues are shown in light blue. A) The predicted interaction surface of a TTR monomer is used for calculation. B) The interface in the native tetrameric structure of TTR is used for calculation (PDB ID:1TTA). C) Dimer of TTR. D) TTR native tetrameric structure. The first dimer is twisted 90° relative to C, the second one is shown in yellow.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719061&req=5

pcbi-1000476-g003: Aggregation and interaction regions in human transthyretin.In all panels, transthyretin (TTR) aggregation-prone residues at less and more than 3 Å from interaction sites are shown in red and green, respectively. Interface residues not included in aggregation-prone regions are shown in dark blue. Rest of residues are shown in light blue. A) The predicted interaction surface of a TTR monomer is used for calculation. B) The interface in the native tetrameric structure of TTR is used for calculation (PDB ID:1TTA). C) Dimer of TTR. D) TTR native tetrameric structure. The first dimer is twisted 90° relative to C, the second one is shown in yellow.
Mentions: A single interaction patch is predicted for the TTR monomer (Figure 3A). It involves 19 residues located in the A β-strand (L17, A19), in the loop between the A and B β-strands (V20–S23), in the α-helix (L82), in the loop between the helix and the F β-strand (S85-F87), in the F β-strand (E92), in the G and H β-strands, and in the loop between the G and H β-strands (L110, S112-T118). TTR is a dimer of dimers. In the dimers formed by the A and B or the C and D chains, the predicted clusters are contiguous, forming a large and continuous interaction patch. Of the residues in aggregation-prone regions in TTR, 41% are within 3 Å of predicted interaction sites (Table 1). With the exception of the I26-R34 fragment, all the regions with high aggregation propensity are located close to the predicted interface, and 30% of the residues in these segments overlap with predicted interaction sites. Residues 17, 19, 92, 110, 112, and the stretch 115–118 are predicted to be important both for aggregation and interaction events.

Bottom Line: The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell.Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates.It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.

View Article: PubMed Central - PubMed

Affiliation: Departament de Bioquímica i Biologia Molecular and Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.

ABSTRACT
Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases. Computational analysis of the native complexes formed by these proteins shows that aggregation-prone regions do frequently overlap with protein interfaces. The spatial coincidence of interaction sites and aggregating regions suggests that the formation of functional complexes and the aggregation of their individual subunits might compete in the cell. Accordingly, single mutations affecting complex interface or stability usually result in the formation of toxic aggregates. It is suggested that the stabilization of existing interfaces in multimeric proteins or the formation of new complexes in monomeric polypeptides might become effective strategies to prevent disease-linked aggregation of globular proteins.

Show MeSH
Related in: MedlinePlus