Cytotoxicity of Aberrant Proteins


A wide range of diseases are caused by the generation of aberrant proteins that for one reason or another are not functionally equivalent to the normal version. Here, we consider the basic cellular principles that govern the generation of aberrant proteins, their normal metabolism and in the case of disease, their adverse effects on cellular function.

Key concepts

  • The organization of proteins inside cells is highly regulated at many levels.

  • Proteins that are not folded correctly or not trafficked to their intended destination are aberrant and have the potential to cause cellular dysfunction.

  • Numerous quality control systems constantly detect and degrade aberrant proteins.

  • Failure to either recognize or promptly degrade aberrant proteins can lead to their accumulation, and in some cases, their aggregation.

  • Misfolded or mislocalized proteins can interact inappropriately with other cellular factors to cause toxicity.

  • Most diseases of protein misfolding probably have multiple mechanisms that operate simultaneously to cause pathology.

Keywords: quality control; protein misfolding diseases; neurodegeneration; protein aggregation; chaperones

Figure 1.

Cellular organization of proteins. An illustration of the multiple layers of cellular organization that must be constantly maintained by biosynthetic and trafficking pathways, and vigilantly monitored by quality control pathways. (a) Eukaryotic cells contain numerous spatially distinct compartments whose environments differ considerably. For example, the endoplasmic reticulum (red) is an oxidizing environment, the cytosol is a reducing environment, the cell surface (yellow) is exposed to the outside, endocytic and lysosomal compartments (green) are acidic, and so on. (b, c) At the molecular level, each compartment is filled with its own unique ensemble of proteins (and other macromolecules) whose precise composition and levels directly impact that compartment's function. For example, the cell surface contains channels and receptors whose identities and amounts directly impact communication between the inside and outside of the cell, while the ER contains machinery for protein translocation (the ‘translocon’). Molecular level organization is also determined by the assembly of many protein constituents into appropriate functional complexes. The ER translocon is depicted as an assembly of a channel component (dark grey) associated with various additional factors in the lumen and membrane. The receptor associates with cytosolic signalling molecules to function. (d) At the atomic level, each protein acquires a precise three‐dimensional folded conformation that allows it to function. Shown is the structure of the channel‐forming component of the ER translocon (a heterotrimeric protein called the Sec61 complex).

Figure 2.

Loss versus gain of function mechanisms. (a) Schematic depiction of the biosynthetic and degradation pathways of a cell surface membrane protein (green) that is initially made at the ER, trafficked through the Golgi to the cell surface, and eventually degraded in the lysosome. (b) In a purely loss of function mechanism, an aberrant version of this same protein (red) would be efficiently recognized and degraded by the cell. Cellular dysfunction is due solely to the absence of the protein. (c) In a gain of function mechanism, the aberrant protein would interact inappropriately with and influence the function of cellular factors not typically encountered by the normal version. In this example, retention of the aberrant protein in the ER allows it to interact with a resident protein (blue) whose altered function is the cause of cellular dysfunction.

Figure 3.

Multiplicity of toxic mechanisms by an aberrant protein. Dominant gain‐of‐function interactions by an aberrant protein (red) can occur in many ways with different partners to cause cellular dysfunction. Most diseases are likely to involve multiple interactions and multiple mechanisms, perhaps explaining their complexity. Some examples are: inappropriate interactions due to altered conformation or residence in an incorrect location (1); failure to be degraded efficiently, generating aggregates that sequester factors (2a) or inhibit organelle function (2b); interaction with and inhibition of QC or degradation machinery (3); generation of metabolites that are toxic (4); performing its function at an incorrect location (5) and interaction with and inhibition of the normal version of the same protein (green) (6).



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Ashok, Aarthi, and Hegde, Ramanujan S(Dec 2008) Cytotoxicity of Aberrant Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020887]