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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 immunoglobulins.In all panels, immunoglobulin (Ig) 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 interface in the native structure of Ig light chain variable domain (LC) is used for calculation (PDB ID: 2Q20). B) Native homodimer of Ig LC, the second monomer is shown in yellow. C) The interface in the native structure of IgG heterotetramer is used for calculation and the Ig heavy chain (HC) represented (PDB ID: 1HZH). D) Native IgG heterotetramer. Ig LCs and the second Ig HC are indicated.
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pcbi-1000476-g005: Aggregation and interaction regions in human immunoglobulins.In all panels, immunoglobulin (Ig) 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 interface in the native structure of Ig light chain variable domain (LC) is used for calculation (PDB ID: 2Q20). B) Native homodimer of Ig LC, the second monomer is shown in yellow. C) The interface in the native structure of IgG heterotetramer is used for calculation and the Ig heavy chain (HC) represented (PDB ID: 1HZH). D) Native IgG heterotetramer. Ig LCs and the second Ig HC are indicated.

Mentions: The light chains (LCs) of immunoglobulins have been implicated in the pathogenesis of amyloidosis in patients with monoclonal B-cell proliferative disorders (AL amyloidosis) [73]. When immunoglobulin molecules are secreted, two heavy chains (HCs) usually pair with two LCs to create a heterotetramer. Occasionally, free LCs are secreted, and these LCs can form homodimers. LC dimers can be innocuous, but they can also aggregate into pathogenic species. We have analyzed the aggregation propensity and interfaces of a non-pathogenic LC dimer (PDB ID: 2Q20) [74]. Five aggregation-prone regions are detected, encompassing residues 19–23, 31–38, 46–51, 71–78, and 84–89 located in the ß3, ß4 ß5, ß9, and ß10 strands, respectively (Table 1). The interface of the dimer involves 13 residues: D34, Y36, Q38, K42-P44, L46, E55, Y87, Q89, Y91, Y96, and F98. According to their IPIs, the second and fifth stretch are located preferentially at the interface of the complex, with 89% and 83% of their residues less than 3 Å from the interface, respectively (Table 1, Figure 1E and Figures 5A, 5B). It is important to note that both stretches map in preformed ß strands.


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 immunoglobulins.In all panels, immunoglobulin (Ig) 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 interface in the native structure of Ig light chain variable domain (LC) is used for calculation (PDB ID: 2Q20). B) Native homodimer of Ig LC, the second monomer is shown in yellow. C) The interface in the native structure of IgG heterotetramer is used for calculation and the Ig heavy chain (HC) represented (PDB ID: 1HZH). D) Native IgG heterotetramer. Ig LCs and the second Ig HC are indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000476-g005: Aggregation and interaction regions in human immunoglobulins.In all panels, immunoglobulin (Ig) 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 interface in the native structure of Ig light chain variable domain (LC) is used for calculation (PDB ID: 2Q20). B) Native homodimer of Ig LC, the second monomer is shown in yellow. C) The interface in the native structure of IgG heterotetramer is used for calculation and the Ig heavy chain (HC) represented (PDB ID: 1HZH). D) Native IgG heterotetramer. Ig LCs and the second Ig HC are indicated.
Mentions: The light chains (LCs) of immunoglobulins have been implicated in the pathogenesis of amyloidosis in patients with monoclonal B-cell proliferative disorders (AL amyloidosis) [73]. When immunoglobulin molecules are secreted, two heavy chains (HCs) usually pair with two LCs to create a heterotetramer. Occasionally, free LCs are secreted, and these LCs can form homodimers. LC dimers can be innocuous, but they can also aggregate into pathogenic species. We have analyzed the aggregation propensity and interfaces of a non-pathogenic LC dimer (PDB ID: 2Q20) [74]. Five aggregation-prone regions are detected, encompassing residues 19–23, 31–38, 46–51, 71–78, and 84–89 located in the ß3, ß4 ß5, ß9, and ß10 strands, respectively (Table 1). The interface of the dimer involves 13 residues: D34, Y36, Q38, K42-P44, L46, E55, Y87, Q89, Y91, Y96, and F98. According to their IPIs, the second and fifth stretch are located preferentially at the interface of the complex, with 89% and 83% of their residues less than 3 Å from the interface, respectively (Table 1, Figure 1E and Figures 5A, 5B). It is important to note that both stretches map in preformed ß strands.

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