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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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Aggregation-prone regions at the interface of selected homodimeric eukaryotic proteins.Aggregation-prone regions in which more than 85% of the residues are at less than 3 Å from the interface are highlighted in green. The PDB ID is indicated for each dimer (see also Table 2).
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pcbi-1000476-g008: Aggregation-prone regions at the interface of selected homodimeric eukaryotic proteins.Aggregation-prone regions in which more than 85% of the residues are at less than 3 Å from the interface are highlighted in green. The PDB ID is indicated for each dimer (see also Table 2).

Mentions: It seems that the spatial coincidence of interfaces and sequences promoting self-assembly is not restricted to amyloidogenic proteins. To further confirm this extent, we analyzed the structure of 25 different eukaryotic proteins shown to form homodimers (Table 2 and Figure 8). As expected, the number of predicted aggregation-prone regions in a protein correlates with its size (R = 0.88). All the analyzed proteins present at least one aggregation segment in which half of the residues are closer than 3 Å to the interface, and 96% of them have at least one aggregation region in which >85% of the residues are adjacent to the interface (Table 2 and Figure 8). This supports the idea that the physico-chemical determinants of aggregation and native self-assembly might overlap significantly and is consistent with the observation that in homodimers, identical monomer subunits tend to associate by hydrophobic interactions [92]. After protein synthesis and folding, monomers probably associate rapidly into native homodimers due to the high local concentration of identical polypeptide chains, thus avoiding prolonged exposure of hydrophobic, aggregation-prone regions to solvent. Interestingly, in heterodimers, in which monomers spend a larger part of their lifetime in a non-associated state, the presence of gatekeeper amino acids (Lys, Arg, Glu, Asp, and Pro) at the complex interface is much greater than in homodimers [92], probably to prevent self-association between identical monomers.


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

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

Aggregation-prone regions at the interface of selected homodimeric eukaryotic proteins.Aggregation-prone regions in which more than 85% of the residues are at less than 3 Å from the interface are highlighted in green. The PDB ID is indicated for each dimer (see also Table 2).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000476-g008: Aggregation-prone regions at the interface of selected homodimeric eukaryotic proteins.Aggregation-prone regions in which more than 85% of the residues are at less than 3 Å from the interface are highlighted in green. The PDB ID is indicated for each dimer (see also Table 2).
Mentions: It seems that the spatial coincidence of interfaces and sequences promoting self-assembly is not restricted to amyloidogenic proteins. To further confirm this extent, we analyzed the structure of 25 different eukaryotic proteins shown to form homodimers (Table 2 and Figure 8). As expected, the number of predicted aggregation-prone regions in a protein correlates with its size (R = 0.88). All the analyzed proteins present at least one aggregation segment in which half of the residues are closer than 3 Å to the interface, and 96% of them have at least one aggregation region in which >85% of the residues are adjacent to the interface (Table 2 and Figure 8). This supports the idea that the physico-chemical determinants of aggregation and native self-assembly might overlap significantly and is consistent with the observation that in homodimers, identical monomer subunits tend to associate by hydrophobic interactions [92]. After protein synthesis and folding, monomers probably associate rapidly into native homodimers due to the high local concentration of identical polypeptide chains, thus avoiding prolonged exposure of hydrophobic, aggregation-prone regions to solvent. Interestingly, in heterodimers, in which monomers spend a larger part of their lifetime in a non-associated state, the presence of gatekeeper amino acids (Lys, Arg, Glu, Asp, and Pro) at the complex interface is much greater than in homodimers [92], probably to prevent self-association between identical monomers.

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