Amino acid homorepeats in proteins

Chavali, Sreenivas; Singh, Anjali Kumari; Balaji, S.; Babu, M. Madan

doi:10.1038/s41570-020-0204-1

Cited by 39 publications

(39 citation statements)

References 147 publications

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“…Homopolymeric amino acid repeats (AARs), such as polyglutamine (polyQ), are increasingly recognized as mediators and regulators of protein function, interactions and evolution (e.g. 1 , 2 , 3 , 4 , 5 , 6 , 7 ). AAR length variation in proteins contributes to intraspecific phenotypic variability and interspecific divergence ( 3 , 5 , 7 , 8 , 9 , 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…While the preferential involvement of polyQ proteins in basic biological processes, such as transcription and translation, is well defined at the cellular and molecular levels (e.g. 4 , 7 ), their functional roles in higher-order biological processes at the organismal level, and their involvement in human diseases besides expansion-related disorders ( 13 ), are still not clearly understood. PolyQ repeats occur frequently in proteins involved in the development of the nervous system ( 12 ) with some degree of regional specificity ( 5 ), suggesting that polyQ variation may have a considerable impact on neural development and evolution.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, it would be important to determine whether the observed evolutionary length variation of AARs, such as polyQ, occurs independently in each protein or, rather, in a more coordinated manner across functionally related proteins, as in an integrated regulatory system. Indeed, polyQ length co-evolution, through coordinated variation in the length and stability of CC structures mediating protein interactions, may have considerable functional impact on polyQ protein networks ( 1 , 4 , 6 , 7 , 25 , 26 , 27 ).…”

Section: Introductionmentioning

confidence: 99%

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PolyQ length co-evolution in neural proteins

Vaglietti

Fiumara

2021

NAR Genomics and Bioinformatics

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Intermolecular co-evolution optimizes physiological performance in functionally related proteins, ultimately increasing molecular co-adaptation and evolutionary fitness. Polyglutamine (polyQ) repeats, which are over-represented in nervous system-related proteins, are increasingly recognized as length-dependent regulators of protein function and interactions, and their length variation contributes to intraspecific phenotypic variability and interspecific divergence. However, it is unclear whether polyQ repeat lengths evolve independently in each protein or rather co-evolve across functionally related protein pairs and networks, as in an integrated regulatory system. To address this issue, we investigated here the length evolution and co-evolution of polyQ repeats in clusters of functionally related and physically interacting neural proteins in Primates. We observed function-/disease-related polyQ repeat enrichment and evolutionary hypervariability in specific neural protein clusters, particularly in the neurocognitive and neuropsychiatric domains. Notably, these analyses detected extensive patterns of intermolecular polyQ length co-evolution in pairs and clusters of functionally related, physically interacting proteins. Moreover, they revealed both direct and inverse polyQ length co-variation in protein pairs, together with complex patterns of coordinated repeat variation in entire polyQ protein sets. These findings uncover a whole system of co-evolving polyQ repeats in neural proteins with direct implications for understanding polyQ-dependent phenotypic variability, neurocognitive evolution and neuropsychiatric disease pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PolyQ length co-evolution in neural proteins

Vaglietti

Fiumara

2021

NAR Genomics and Bioinformatics

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“…Here, we demonstrate that CF protein synthesis is an extremely well-suited platform for the structural investigation of LCRs by NMR. To demonstrate this point, we have studied HttEx1, arguably the most notorious example of homorepeat proteins [ 82 , 83 , 84 ] due to the direct link between the size of the poly-Q and the appearance of neurodegenerative HD.…”

Section: Discussionmentioning

confidence: 99%

Robust Cell-Free Expression of Sub-Pathological and Pathological Huntingtin Exon-1 for NMR Studies. General Approaches for the Isotopic Labeling of Low-Complexity Proteins

et al. 2020

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The high-resolution structural study of huntingtin exon-1 (HttEx1) has long been hampered by its intrinsic properties. In addition to being prone to aggregate, HttEx1 contains low-complexity regions (LCRs) and is intrinsically disordered, ruling out several standard structural biology approaches. Here, we use a cell-free (CF) protein expression system to robustly and rapidly synthesize (sub-) pathological HttEx1. The open nature of the CF reaction allows the application of different isotopic labeling schemes, making HttEx1 amenable for nuclear magnetic resonance studies. While uniform and selective labeling facilitate the sequential assignment of HttEx1, combining CF expression with nonsense suppression allows the site-specific incorporation of a single labeled residue, making possible the detailed investigation of the LCRs. To optimize CF suppression yields, we analyze the expression and suppression kinetics, revealing that high concentrations of loaded suppressor tRNA have a negative impact on the final reaction yield. The optimized CF protein expression and suppression system is very versatile and well suited to produce challenging proteins with LCRs in order to enable the characterization of their structure and dynamics.

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“…[16] In recent years, TME-activated enzyme dynamic therapy, [17] as a burgeoning reactive oxygen species (ROS)-based dynamic therapy model, [18] has attracted extensive attention. [19] Natural enzymes in living organisms are proteins composed of several hundred amino acids, [20] which have quite high catalytic activity and substrate specificity. [21] Nanozyme is a kind of nanomaterial with enzyme catalytic properties, [22] which has drawn lots of attention due to the advantages of stability, [23] low cost [24] and adjustable enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu_2‐xSe−GOx for Cervical Cancer Therapy

Wang

2021

Chemistry A European J

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Cervical cancer, as a common malignant tumor of the reproductive system, seriously threatens women's life and health, and is difficult to be cured by traditional treatments, such as surgery, chemotherapy and radiotherapy. Fortunately, tumor microenvironment (TME)-activated catalytic therapy with high efficiency and reduced off-target toxicity has emerged as a novel treatment model. Herein, we designed a "four-in-one" nanozyme and natural enzyme symbiotic system of Cu 2-x SeÀ GOx for TME-triggered cascaded catalytic enhanced cancer treatment. In response to unique TME, Cu 2-x Se with catalase activity could effectively catalyze over-expressed H 2 O 2 in cancer cells into O 2 . Subsequently, the glucose oxidase (GOx) could deplete intracellular glucose with the assistance of O 2 ; this not only achieves starvation therapy, but also regenerates H 2 O 2 to boost the generation of highly cytotoxic * OH due to the peroxidase activity of Cu 2-x Se. Moreover, although the free-radical scavenger glutathione (GSH) is overexpressed in tumor cells, Cu 2-x Se with glutathione oxidase activity could effectively consume GSH for enhanced ROS production. Thus, the "four-in-one" nanozyme@natural enzyme symbiotic system of Cu 2-x SeÀ GOx could induce significant ROS accumulation at the tumor regions, thus providing a potential approach for the treatment of cervical cancer.

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Amino acid homorepeats in proteins

Cited by 39 publications

References 147 publications

PolyQ length co-evolution in neural proteins

PolyQ length co-evolution in neural proteins

Robust Cell-Free Expression of Sub-Pathological and Pathological Huntingtin Exon-1 for NMR Studies. General Approaches for the Isotopic Labeling of Low-Complexity Proteins

“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu_2‐xSe−GOx for Cervical Cancer Therapy

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Amino acid homorepeats in proteins

Cited by 39 publications

References 147 publications

PolyQ length co-evolution in neural proteins

PolyQ length co-evolution in neural proteins

Robust Cell-Free Expression of Sub-Pathological and Pathological Huntingtin Exon-1 for NMR Studies. General Approaches for the Isotopic Labeling of Low-Complexity Proteins

“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu2‐xSe−GOx for Cervical Cancer Therapy

Contact Info

Product

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“Four‐in‐One” Nanozyme and Natural Enzyme Symbiotic System of Cu_2‐xSe−GOx for Cervical Cancer Therapy