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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

New interfaces at human lysozyme and Aß peptide aggregation-prone regions.In all panels, 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 lysozyme is used for calculation. B) The interface between lysozyme and a camelid antibody is used for calculation (PDB ID: 1OP9). C) Lysozyme complex with a camelid antibody. D) Ribbon representation of Aß peptide. The interface between the peptide and a designed affibody is used for calculation (PDB ID: 2OTK). E) Aß peptide bound to a designed affibody.
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pcbi-1000476-g006: New interfaces at human lysozyme and Aß peptide aggregation-prone regions.In all panels, 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 lysozyme is used for calculation. B) The interface between lysozyme and a camelid antibody is used for calculation (PDB ID: 1OP9). C) Lysozyme complex with a camelid antibody. D) Ribbon representation of Aß peptide. The interface between the peptide and a designed affibody is used for calculation (PDB ID: 2OTK). E) Aß peptide bound to a designed affibody.

Mentions: Two different interaction clusters are predicted for human lysozyme (Figure 6A), one in the α-domain and the other in the ß-domain. The first involves residues in the loop of the β-domain: N60, R62-W64, N66, A73-N75, A76, and H78. The second cluster is located in helix C and around helix D and corresponds to residues A94, K97, R98, R107-W109, and W112. Residues K33 and W34 in helix B are also predicted to be involved in protein-protein interactions. Overall, 66% of the residues in regions with high aggregation propensity are less than 3 Å from predicted interaction sites, and 31% overlap with them. Residues 33, 60, 62–64, 66, 76, 78, 108, 109, and 112 might be implicated in both binding and aggregation reactions. Interestingly, residues I56, F57, W64, and D67, which are mutated in the four known single-residue familial variants associated with lysozyme amyloidosis, are comprised of or very close to protein segments with high aggregation propensity and/or interaction sites.


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

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

New interfaces at human lysozyme and Aß peptide aggregation-prone regions.In all panels, 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 lysozyme is used for calculation. B) The interface between lysozyme and a camelid antibody is used for calculation (PDB ID: 1OP9). C) Lysozyme complex with a camelid antibody. D) Ribbon representation of Aß peptide. The interface between the peptide and a designed affibody is used for calculation (PDB ID: 2OTK). E) Aß peptide bound to a designed affibody.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000476-g006: New interfaces at human lysozyme and Aß peptide aggregation-prone regions.In all panels, 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 lysozyme is used for calculation. B) The interface between lysozyme and a camelid antibody is used for calculation (PDB ID: 1OP9). C) Lysozyme complex with a camelid antibody. D) Ribbon representation of Aß peptide. The interface between the peptide and a designed affibody is used for calculation (PDB ID: 2OTK). E) Aß peptide bound to a designed affibody.
Mentions: Two different interaction clusters are predicted for human lysozyme (Figure 6A), one in the α-domain and the other in the ß-domain. The first involves residues in the loop of the β-domain: N60, R62-W64, N66, A73-N75, A76, and H78. The second cluster is located in helix C and around helix D and corresponds to residues A94, K97, R98, R107-W109, and W112. Residues K33 and W34 in helix B are also predicted to be involved in protein-protein interactions. Overall, 66% of the residues in regions with high aggregation propensity are less than 3 Å from predicted interaction sites, and 31% overlap with them. Residues 33, 60, 62–64, 66, 76, 78, 108, 109, and 112 might be implicated in both binding and aggregation reactions. Interestingly, residues I56, F57, W64, and D67, which are mutated in the four known single-residue familial variants associated with lysozyme amyloidosis, are comprised of or very close to protein segments with high aggregation propensity and/or interaction sites.

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