1. Motif 是多個二級結構形成重複性的結構單位。
是多個二級結構所呈現規律性的結構單位，
此單位可能重複的出現於同一蛋白質中，
或見於多種不同的蛋白質中者，
便可稱為一種特定的 motif。
在motif的層次上，主要是強調結構的概念而不是功能，
因此多種不同的蛋白質，也可能具有相同名字的motif。
課本 (Campbell 5th) 將motif視為重複性超二級結構
(repetitive supersecondary structure)。
註：supersecondary structure Link
超二級結構是介於蛋白質二級結構和三級結構之間的空間結構,
指相鄰的二級結構單元組合在一起，彼此相互作用，排列形成規則的、
在空間結構上能夠辨認的二級結構組合體，並充當三級結構的構件
（block building），其基本形式有αα、βαβ和βββ等。 多數情況下只
有非極性殘基側鏈參與這些相互作用,而親水側鏈多在分子的外表面。
2. Domain 蛋白質中『局部的』立體結構所呈現獨立的功能單位。
例如：酵素分子中可能具有
a. catalytic domain 主要表現活性的立體位置；
b. regulatory domain 主要表現調節的區域。
domain 是指蛋白質中『局部的』三級結構，
比較強調的是功能單位，因此多半是以『功能』做為稱呼domain的名字。
2012年11月27日 星期二
2012年11月2日 星期五
Protein aggregation
Cause Link
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.
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.
2012年10月30日 星期二
Write 1 Bin
來自引述 WCN 的 paper - Using catalytic atom maps to predict .........
Seven bins for each data set
Seven bins for each data set
2012年10月24日 星期三
2012年10月23日 星期二
aggregation region
Find the aggregation region in thermophilic protein ( PDB )
1. WCN
2. Hydrophobic
3. Conservation
4. B-factor
5. CN (cutoff 9 angstrom)
6. RSA
1. WCN
2. Hydrophobic
3. Conservation
4. B-factor
5. CN (cutoff 9 angstrom)
6. RSA
催化 catalytic site
結構相關因子:
pocket, RSA, rigidity, packing density (WCN),
fixed geometry (structure conserved , distance, angle -> function )
降低活化能 free energy barrier
加速化學反應
ref.
Coupling between Catalytic Site and Collective Dynamics: A Requirement for Mechanochemical Activity of Enzymes
pocket, RSA, rigidity, packing density (WCN),
fixed geometry (structure conserved , distance, angle -> function )
降低活化能 free energy barrier
加速化學反應
ref.
Coupling between Catalytic Site and Collective Dynamics: A Requirement for Mechanochemical Activity of Enzymes
2012年10月2日 星期二
Zhiping Weng
Structure, function, and evolution of transient and obligate protein–protein interactions Link
Recent analyses of high-throughput protein interaction data coupled with large-scale investigations of evolutionary properties of interaction networks have left some unanswered questions. To what extent do protein interactions act as constraints during evolution of the protein sequence? How does the type of interaction, specifically transient or obligate, play into these constraints? Are the mutations in the binding site of an interacting protein correlated with mutations in the binding site of its partner? We address these and other questions by relying on a carefully curated dataset of protein complex structures. Results point to the importance of distinguishing between transient and obligate interactions. We conclude that residues in the interfaces of obligate complexes tend to evolve at a relatively slower rate, allowing them to coevolve with their interacting partners. In contrast, the plasticity inherent in transient interactions leads to an increased rate of substitution for the interface residues and leaves little or no evidence of correlated mutations across the interface.
LabLink
Recent analyses of high-throughput protein interaction data coupled with large-scale investigations of evolutionary properties of interaction networks have left some unanswered questions. To what extent do protein interactions act as constraints during evolution of the protein sequence? How does the type of interaction, specifically transient or obligate, play into these constraints? Are the mutations in the binding site of an interacting protein correlated with mutations in the binding site of its partner? We address these and other questions by relying on a carefully curated dataset of protein complex structures. Results point to the importance of distinguishing between transient and obligate interactions. We conclude that residues in the interfaces of obligate complexes tend to evolve at a relatively slower rate, allowing them to coevolve with their interacting partners. In contrast, the plasticity inherent in transient interactions leads to an increased rate of substitution for the interface residues and leaves little or no evidence of correlated mutations across the interface.
LabLink
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