2012年11月2日 星期五

Protein aggregation

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Protein aggregation can occur due to a variety of causes. Individuals may have mutations that encode for proteins that are particularly sensitive to misfolding and aggregation. Alternatively, disruption of the pathways to refold proteins (chaperones) or to degrade misfolded proteins (the ubiquitin-proteasome pathway) may lead to protein aggregation. As many of the diseases associated with protein aggregation increase in frequency with age, it seems that cells lose the ability to clear misfolded proteins and aggregates over time. Several new studies suggests that protein aggregation is a second line of the cellular reaction to an imbalanced protein homeostasis rather than a harmful, random process.[7]. A groundbreaking study[8] showed that sequestration of misfolded, aggregation-prone proteins into inclusion sites is an active organized cellular process, that depends on quality control components, such as HSPs and co-chaperones. Moreover, it was shown that eukaryotic cells have the ability to sort misfolded proteins in to two quality control compartments: 1. The JUNQ (JUxta Nuclear Quality control compartment). 2. The IPOD (Insoluble Protein Deposit). The partition into two quality control compartments is due to the different handling and processing of the different kinds of misfolded aggregative proteins: The IPOD serves as a sequestration site for non-ubiquitinated terminally aggregated proteins, such as the huntingtin protein. Under stress conditions, such as heat, when the cellular quality control machinery is saturated, ubiquitinated proteins are sorted to the JUNQ compartment, where they are eventually degraded. Thus, aggregation is a regulated, controlled process.



Exposed hydrophobicity is a key determinant of nuclear quality control degradation

Protein quality control (PQC) degradation protects the cell by preventing the toxic accumulation of misfolded proteins. In eukaryotes, PQC degradation is primarily achieved by ubiquitin ligases that attach ubiquitin to misfolded proteins for proteasome degradation. To function effectively, PQC ubiquitin ligases must distinguish misfolded proteins from their normal counterparts by recognizing an attribute of structural abnormality commonly shared among misfolded proteins. However, the nature of the structurally abnormal feature recognized by most PQC ubiquitin ligases is unknown. Here we demonstrate that the yeast nuclear PQC ubiquitin ligase San1 recognizes exposed hydrophobicity in its substrates. San1 recognition is triggered by exposure of as few as five contiguous hydrophobic residues, which defines the minimum window of hydrophobicity required for San1 targeting. We also find that the exposed hydrophobicity recognized by San1 can cause aggregation and cellular toxicity, underscoring the fundamental protective role for San1-mediated PQC degradation of misfolded nuclear proteins. 



Amyloidogenic Regions and Interaction Surfaces Overlap in Globular Proteins Related to Conformational Diseases

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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