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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 SOD1.In panels A, B and C SOD1 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 SOD1 monomer is used for calculation. B) The interface in the native dimeric structure of SOD1 is used for calculation (PDB ID:2C9V). C) Native dimer of SOD1, the second monomer is shown in yellow. D) Ribbon representation of the SOD1 dimer, predicted aggregation-prone regions are shown in red.
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pcbi-1000476-g004: Aggregation and interaction regions in human SOD1.In panels A, B and C SOD1 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 SOD1 monomer is used for calculation. B) The interface in the native dimeric structure of SOD1 is used for calculation (PDB ID:2C9V). C) Native dimer of SOD1, the second monomer is shown in yellow. D) Ribbon representation of the SOD1 dimer, predicted aggregation-prone regions are shown in red.

Mentions: A total of 14 residues are predicted to be at the interface of the SOD1 monomer (Figure 4A). They correspond to E21, W32, G33, S105, S107, G108, H110, C111, I113-R115, G147, V148, and I151. Of the residues in aggregation-prone regions in SOD1, 61% are less than 3 Å from predicted interaction sites (Table 1), and 25% of them overlap the predicted interaction sites. In particular, residues 105, 111, 113, 114, 115, 147, 148, and 151 are predicted to be involved in both binding and aggregation.


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 SOD1.In panels A, B and C SOD1 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 SOD1 monomer is used for calculation. B) The interface in the native dimeric structure of SOD1 is used for calculation (PDB ID:2C9V). C) Native dimer of SOD1, the second monomer is shown in yellow. D) Ribbon representation of the SOD1 dimer, predicted aggregation-prone regions are shown in red.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000476-g004: Aggregation and interaction regions in human SOD1.In panels A, B and C SOD1 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 SOD1 monomer is used for calculation. B) The interface in the native dimeric structure of SOD1 is used for calculation (PDB ID:2C9V). C) Native dimer of SOD1, the second monomer is shown in yellow. D) Ribbon representation of the SOD1 dimer, predicted aggregation-prone regions are shown in red.
Mentions: A total of 14 residues are predicted to be at the interface of the SOD1 monomer (Figure 4A). They correspond to E21, W32, G33, S105, S107, G108, H110, C111, I113-R115, G147, V148, and I151. Of the residues in aggregation-prone regions in SOD1, 61% are less than 3 Å from predicted interaction sites (Table 1), and 25% of them overlap the predicted interaction sites. In particular, residues 105, 111, 113, 114, 115, 147, 148, and 151 are predicted to be involved in both binding and aggregation.

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