ATP Can Efficiently Stabilize Protein through a Unique Mechanism

Ou, Xinwen; Lao, Yichong; Xu, Junjie; Wutthinitikornkit, Yanee; Shi, Rui; Chen, Xiangjun; Li, Jingyuan

doi:10.1021/jacsau.1c00316

Cited by 38 publications

(44 citation statements)

References 80 publications

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“…These abundant cationic linkers effectively promote the self-association of ATPs and enhance the formation of large ATP clusters around proteins. It is consistent with our previous work on ubiquitin and dehydrogenase, which has been verified by NMR experiments …”

Section: Resultssupporting

confidence: 93%

“…Particularly, whether there exist certain residues to regulate ATP binding. Additionally, as indicated in our previous work, the ATPs binding to proteins can aggregate into clusters, which is consistent with the self-association of ATP in the aqueous solution. ,− That is to say, the interaction among ATPs may affect their binding to proteins. Besides, the conformation of ATP exhibits considerable flexibility. ,− ATP can take the stretched conformation as well as the bent conformation wherein the adenine interacts with the triphosphate as mediated by metal cations. ,, Hence, it is also worth studying the impact of the flexibility of ATP on self-association and the interaction with proteins.…”

Section: Introductionsupporting

confidence: 86%

“…That is to say, the self-association allows the negatively charged ATP to considerably accumulate around the proteins with distinct net charges by adjusting the proportion of directly bound ATPs in the cluster. It is worth noting that some experimental studies also indicated that ATP–protein interaction had at least a partial electrostatic contribution. , And our previous study on lysozyme, ubiquitin, and malate dehydrogenase has shown that ATP tends to bind to the surface region enriched with positively charged residues . In other words, although the interactions of ATP with various proteins are nonspecific, ATP still exhibits a binding preference for certain regions of these proteins.…”

Section: Resultsmentioning

confidence: 97%

“…Molecular dynamics (MD) simulation serves as an efficient approach to studying the interaction between protein and small molecules such as ATP. − Our previous work revealed a unique mechanism of ATP inhibiting the thermal aggregation of folded proteins (e.g., lysozyme, ubiquitin, and malate dehydrogenase) . ATP tends to bind to the flexible regions enriched with positively charged residues and further aggregates into clusters to stabilize the proteins . However, systematic studies on the ATP binding to various proteins and the comparison are still limited.…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic Insight on General Protein-Binding Ability of ATP and the Impacts of Arginine Residues

2022

J. Phys. Chem. B

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Recent experiments suggested that adenosine triphosphate (ATP) can regulate liquid–liquid phase separation (LLPS) of various proteins and inhibit protein aggregations at its physiological concentration, which is highly correlated with the nonspecific interactions of ATP to a wide variety of proteins. However, the mechanism underlying the general binding capability of ATP largely remains unclear. In this work, we used molecular dynamics simulation to study the binding of ATPs to three proteins with distinct net charges: TDP-43 NTD (−7 e), TAF15-RRM (0 e), HWEL (+8 e). Negatively charged ATP exhibits a strong trend to accumulate around all of these proteins. While only a fraction of the accumulated ATPs directly binds to the limited regions of the protein surface, additional ATPs indirectly bind to proteins by aggregating into ATP clusters. Hence, the proportion of the directly bound ATPs in the clusters as well as their binding regions can be adjusted in response to different proteins, which makes ATP well adapted to a variety of proteins. Moreover, our results suggest that ATP tightly binds to Arg with high affinity, and Arg dominates the direct binding of ATP. Meanwhile, Arg also affects the self-association of accumulated ATPs. The size of the ATP cluster is effectively regulated by the distribution of Arg. Considering the ubiquity of Arg in proteins, our findings are helpful to understand the general binding capability of ATP.

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Section: Resultssupporting

confidence: 93%

Section: Introductionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Mechanistic Insight on General Protein-Binding Ability of ATP and the Impacts of Arginine Residues

2022

J. Phys. Chem. B

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“…Membraneless condensates are also formed by the interaction of ATP with a number of short peptides [8], with actin [56], immunoglobulin [57]. ATP tends to bind to the most flexible and hydrated regions of the polypeptide chain, and this interaction of ATP with proteins is physically universal [58]. The result of this interaction is also probably universal: in most cases, membraneless condensates (organelles, coacervate droplets) are formed.…”

Section: Is There Bound Water In Membraneless Condensates?mentioning

confidence: 99%

Membraneless physiology of the living cell. The past and the present

Matveev

2022

4open

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Since the 1880s, the concept of compartmentalizing through membranes has taken a firm place in cell physiology and has defined the objects, methods, and goals of physiologists’ research for decades. A huge mass of biologists know about the important role of intra-membrane pumps, channels, and lipids, and various hypotheses about the origin of life often begin with explanations about how the lipid membrane occurred, without which it is impossible to imagine the origin of a living cell. Against this background, there was a dissonance of statements that there are membraneless organelles in the cell, the functions of which are rapidly expanding under our eyes. Physically, they are similar to coacervate droplets, which from time to time were used to explain the origin of life, and now the coacervates are being more and more often discussed when describing the physics of the nucleus and cytoplasm of modern cells. However, ideas about the coacervate nature of cytoplasm/protoplasm originated in the first half of the 19th Century, when the contents of cells were likened to jelly, but this approach gradually faded into the shadows. Nevertheless, limited research in this area continued and was completed in the form of a membraneless cell physiology. Now that the focus of attention has turned to membraneless compartmentalization, it’s time to remember the past. The sorption properties of proteins are the physical basis of membraneless cell because of water adsorbed by proteins changes the physical state of any biomolecular system, from supramolecular and subcellular structures to the cell as a whole. A thermodynamic aqueous phase is formed because adsorbed water does not mix with ordinary water and, in this cause, is separated from the surrounding solution in the form of a compartment. This article discusses the fundamental physical properties of such a phase – a biophase. As it turned out, the Meyer–Overton rule, which led to the idea of a lipid membrane, also applies to membraneless condensates.

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Insights From a Novel Splicing Variant and Recurrent Arginine Variants in the CHD3 Gene Causing Snijders Blok–Campeau Syndrome

Tie,

Che,

Liu

et al. 2024

American J of Med Genetics Pt A

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Snijders Blok–Campeau syndrome (SNIBCPS, OMIM#618205) is an autosomal dominant neurodevelopmental disorder attributed to pathogenic variants in the chromodomain helicase DNA binding protein 3 (CHD3) gene. To date, more than 100 individuals have been diagnosed with SNIBCPS. The syndrome is characterized by intellectual disability, global developmental delay, speech or language impediments, and dysmorphic features associated with macrocephaly. Additionally, affected individuals may exhibit behavioral issues, hypotonia, and autistic traits. A novel splicing variant (c.5590+1G > T) in the C‐terminal 2 region of the CHD3 gene was identified in a patient predominantly exhibiting autistic characteristics. In vitro minigene splicing experiments conducted in HEK293 cells revealed that aberrant splicing resulted in the formation of a cryptic site 46 nucleotides downstream of the 5′ splice site. This alteration was predicted to disrupt the reading frame by eliminating the physiological stop codon, consequently causing an extension in protein translation. Furthermore, an additional patient presenting with hypotonia, dysmorphic features, and global developmental delay was documented. This patient harbored a missense variant in the helicase C‐terminal domain, c.3505C > T (p. Arg1169Trp). The pathogenic variant was anticipated to impact chromatin remodeling capacity and enzyme activity. Given the high prevalence of arginine residue pathogenic variants in the CHD3 protein and its notable propensity for binding and storing ATP molecules, intriguing insights into the potential effects of arginine residue pathogenic variants on phenotypes are provided. These findings contribute to a more comprehensive understanding of the genetic landscape of SNIBCPS while elucidating potential molecular mechanisms underlying the syndrome.

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ATP Can Efficiently Stabilize Protein through a Unique Mechanism

Cited by 38 publications

References 80 publications

Mechanistic Insight on General Protein-Binding Ability of ATP and the Impacts of Arginine Residues

Mechanistic Insight on General Protein-Binding Ability of ATP and the Impacts of Arginine Residues

Membraneless physiology of the living cell. The past and the present

Insights From a Novel Splicing Variant and Recurrent Arginine Variants in the CHD3 Gene Causing Snijders Blok–Campeau Syndrome

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