Metal Ions and Intrinsically Disordered Proteins and Peptides: From Cu/Zn Amyloid-尾 to General Principles
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- 作者：Peter Faller ; Christelle Hureau ; Giovanni La Penna
- 刊名：Accounts of Chemical Research
- 出版年：2014
- 出版时间：August 19, 2014
- 年：2014
- 卷：47
- 期：8
- 页码：2252-2259
- 全文大小：390K
- ISSN：1520-4898
文摘
Conspectus
The interaction of d-block metal ions (Cu, Zn, Fe, etc.) with intrinsically disordered proteins (IDPs) has gained interest, partly due to their proposed roles in several diseases, mainly neurodegenerative. A prominent member of IDPs is the peptide amyloid-尾 (A尾) that aggregates into metal-enriched amyloid plaques, a hallmark of Alzheimer鈥檚 disease, in which Cu and Zn are bound to A尾.
IDPs are a class of proteins and peptides that lack a unique 3D structure when the protein is isolated. This disordered structure impacts their interaction with metal ions compared with structured metalloproteins. Metalloproteins either have a preorganized metal binding site or fold upon metal binding, resulting in defined 3D structure with a well-defined metal site. In contrast, for A尾 and likely most of the other IDPs, the affinity for Cu(I/II) and Zn(II) is weaker and the interaction is flexible with different coordination sites present. Coordination of Cu(I/II) with A尾 is very dynamic including fast Cu-exchange reactions (milliseconds or less) that are intrapeptidic between different sites as well as interpeptidic.
This highly dynamic metal鈥揑DP interaction has a strong impact on reactivity and potential biological role: (i) Due to the low affinity compared with classical metalloproteins, IDPs likely bind metals only at special places or under special conditions. For A尾, this is likely in the neurons that expel Zn or Cu into the synapse and upon metal dysregulation occurring in Alzheimer鈥檚 disease. (ii) Amino acid substitutions (mutations) on noncoordinating residues can change drastically the coordination sphere. (iii) Considering the Cu/Zn鈥揂尾 aberrant interaction, therapeutic strategies can be based on removal of Cu/Zn or precluding their binding to the peptide. The latter is very difficult due to the multitude of metal-binding sites, but the fast koff facilitates removal. (iv) The high flexibility of the Cu鈥揂尾 complex results in different conformations with different redox activity. Only some conformations are able to produce reactive oxygen species. (v) Other, more specific catalysis (like enzymes) is very unlikely for Cu/Zn鈥揂尾. (vi) The Cu/Zn exchange reactions with A尾 are faster than the aggregation process and can hence have a strong impact on this process.
In conclusion, the coordination chemistry is fundamentally different for most of IDPs compared with the classical, structured metalloproteins or with (bio)-inorganic complexes. The dynamics is a key parameter to understand this interaction and its potential biological impact.
The interaction of d-block metal ions (Cu, Zn, Fe, etc.) with intrinsically disordered proteins (IDPs) has gained interest, partly due to their proposed roles in several diseases, mainly neurodegenerative. A prominent member of IDPs is the peptide amyloid-尾 (A尾) that aggregates into metal-enriched amyloid plaques, a hallmark of Alzheimer鈥檚 disease, in which Cu and Zn are bound to A尾.
IDPs are a class of proteins and peptides that lack a unique 3D structure when the protein is isolated. This disordered structure impacts their interaction with metal ions compared with structured metalloproteins. Metalloproteins either have a preorganized metal binding site or fold upon metal binding, resulting in defined 3D structure with a well-defined metal site. In contrast, for A尾 and likely most of the other IDPs, the affinity for Cu(I/II) and Zn(II) is weaker and the interaction is flexible with different coordination sites present. Coordination of Cu(I/II) with A尾 is very dynamic including fast Cu-exchange reactions (milliseconds or less) that are intrapeptidic between different sites as well as interpeptidic.
This highly dynamic metal鈥揑DP interaction has a strong impact on reactivity and potential biological role: (i) Due to the low affinity compared with classical metalloproteins, IDPs likely bind metals only at special places or under special conditions. For A尾, this is likely in the neurons that expel Zn or Cu into the synapse and upon metal dysregulation occurring in Alzheimer鈥檚 disease. (ii) Amino acid substitutions (mutations) on noncoordinating residues can change drastically the coordination sphere. (iii) Considering the Cu/Zn鈥揂尾 aberrant interaction, therapeutic strategies can be based on removal of Cu/Zn or precluding their binding to the peptide. The latter is very difficult due to the multitude of metal-binding sites, but the fast koff facilitates removal. (iv) The high flexibility of the Cu鈥揂尾 complex results in different conformations with different redox activity. Only some conformations are able to produce reactive oxygen species. (v) Other, more specific catalysis (like enzymes) is very unlikely for Cu/Zn鈥揂尾. (vi) The Cu/Zn exchange reactions with A尾 are faster than the aggregation process and can hence have a strong impact on this process.
In conclusion, the coordination chemistry is fundamentally different for most of IDPs compared with the classical, structured metalloproteins or with (bio)-inorganic complexes. The dynamics is a key parameter to understand this interaction and its potential biological impact.