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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 ß2-microglobulin.In all panels, β2-microglobulin 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 for monomeric β2-microglobulin is used for calculation. B) The interface between β2-microglobulin and HLA heavy chain is used for calculation (PDB ID:1DUZ). C) The interface between β2-microglobulin and HFE is used for calculation (PDB ID:1A6Z). D and E) Front (same orientation that in B) and back view of the β2-microglobulin/HLA heavy chain complex. F and G) Front (same orientation that in C) and back view of the β2-microglobulin/HFE complex.
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pcbi-1000476-g002: Aggregation and interaction regions in human ß2-microglobulin.In all panels, β2-microglobulin 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 for monomeric β2-microglobulin is used for calculation. B) The interface between β2-microglobulin and HLA heavy chain is used for calculation (PDB ID:1DUZ). C) The interface between β2-microglobulin and HFE is used for calculation (PDB ID:1A6Z). D and E) Front (same orientation that in B) and back view of the β2-microglobulin/HLA heavy chain complex. F and G) Front (same orientation that in C) and back view of the β2-microglobulin/HFE complex.

Mentions: Amyloidosis related to β2-Microglobulin (β2-m) is a common and serious complication in patients on long-term hemodialysis [46]. Two aggregation-prone regions encompassing residues 22–31 and 60–70 were predicted for human β2-m (Figure 2). These regions neatly coincide with two secondary structure elements in β2-m: β-strand 2, formed by residues 21–31, and β-strand 6, formed by residues 61–71. Interestingly, most of the residues in these two regions appear to be solvent accessible (Table 1). In agreement with the prediction, the fragments 21–31 and 21–41 of β2-m self-assemble into fibrillar structures [47]. Also, a peptide corresponding to residues 59–79 and its shorter version 59–71 both form amyloid fibrils [48].


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 ß2-microglobulin.In all panels, β2-microglobulin 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 for monomeric β2-microglobulin is used for calculation. B) The interface between β2-microglobulin and HLA heavy chain is used for calculation (PDB ID:1DUZ). C) The interface between β2-microglobulin and HFE is used for calculation (PDB ID:1A6Z). D and E) Front (same orientation that in B) and back view of the β2-microglobulin/HLA heavy chain complex. F and G) Front (same orientation that in C) and back view of the β2-microglobulin/HFE complex.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000476-g002: Aggregation and interaction regions in human ß2-microglobulin.In all panels, β2-microglobulin 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 for monomeric β2-microglobulin is used for calculation. B) The interface between β2-microglobulin and HLA heavy chain is used for calculation (PDB ID:1DUZ). C) The interface between β2-microglobulin and HFE is used for calculation (PDB ID:1A6Z). D and E) Front (same orientation that in B) and back view of the β2-microglobulin/HLA heavy chain complex. F and G) Front (same orientation that in C) and back view of the β2-microglobulin/HFE complex.
Mentions: Amyloidosis related to β2-Microglobulin (β2-m) is a common and serious complication in patients on long-term hemodialysis [46]. Two aggregation-prone regions encompassing residues 22–31 and 60–70 were predicted for human β2-m (Figure 2). These regions neatly coincide with two secondary structure elements in β2-m: β-strand 2, formed by residues 21–31, and β-strand 6, formed by residues 61–71. Interestingly, most of the residues in these two regions appear to be solvent accessible (Table 1). In agreement with the prediction, the fragments 21–31 and 21–41 of β2-m self-assemble into fibrillar structures [47]. Also, a peptide corresponding to residues 59–79 and its shorter version 59–71 both form amyloid fibrils [48].

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