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Key Event: 2234

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Binding of C6R-Derived Protein K7

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
cell

Organ term

Organ term
organ

Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
C6R-Derived Protein K7 following Monkeypox infection leads to heart failure	MolecularInitiatingEvent	Arthur Author (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
Mustela lutreola	Mustela lutreola	Low	NCBI
Felis catus	Felis catus	Low	NCBI
Panthera tigris	Panthera tigris	Low	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult, reproductively mature	High
During brain development, adulthood and aging	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The binding of C6R-derived protein K7 utilizes specific molecular interactions that allows it to attach to a receptor, inhibitor, or another protein. The C6R sequence from which the K7 protein is derived is potentially a binding candidate for molecule S31-201. (Loganathan et. al, 2024).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Analysis of protein K7 can show the structures of the wild-type and the mutant form of the protein. Chiron energy can be used to optimize these structures. (Ramachandran et. al, 2011). After the structures are formed, a Ramachandran plot can be used to validate the proposed optimized structure. (Kumar et. al, 2023). In order to understand the effects of mutations on K7, FoldX is used to buidling mutant models and its respective structural repair. (Buß et. al, 2018). Pertubation by stressor occurs due to the dissipation of the binding zone for the C6R-derived protein K7 which can be caused by environmental stressors.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic:

This KE is applicable to several species and the overall evidence supporting taxonomic applicability is moderate. The binding of C6R-Derived Protein K7 and utilizes the S3I-201. (Loganathan et. al, 2024). Moreover, their crucial role in the development activating cellular antiviral defenses through histone modification. However, the role of this KE in monkeypox depends on the expression and function of specific proteins, such as the C6R-expressed protein K7, which may vary across species and tissues. Extrapolation for cross-species and unique developmental stages should be applied with caution.

Life stage:

Because applications of the C6R-expressed protein K7 typically occurs during the later stages of the viral replication cycle, it is quite common for it to include immune modulation. As a result, monkeys and apes were primarily shown to have this virus (Arita et al., 1968). In terms of human infection, the first case occured in a 9 month old boy in the Congo. (Ladnyj et al., 1972). Because of the compelxity of the monkeypox genome (196kbp-211 kbp), its domain of applicability may vary depending on the sequence portion that is being mutated. It is still uncertain whether or not the C6R-expressed protein K7 is activated in other processes and how this determines the overall sensitivity the immune modulation.

Sex:

The KE is plausibly applicable to both sexes. The expression and binding of the C6R-expressed protein K7 can have sex-dependent differences in the sensitivity due to the amount of expression of the K7 protein and conseuqently the modulation of the histones. While it mostly occurs in males, there is a small possiblity that the expression of this protein can occur in females as well. (Vallejo-Plaza A et. al, 2022).

References

List of the literature that was cited for this KE description. More help

Buß, O., Rudat, J., & Ochsenreither, K. (2018). FoldX as Protein Engineering Tool: Better Than Random Based Approaches? Computational and Structural Biotechnology Journal, 16, 25–33. https://doi.org/10.1016/J.CSBJ.2018.01.002

Kumar, R., Nagar, S., Haider, S., Sood, U., Ponnusamy, K., Dhingra, G. G., Anand, S., Dua, A., Singh, M., Kumar, R., Sengar, M., Singh, I. K., & Lal, R. (2023). Monkeypox virus: phylogenomics, host-pathogen interactome and mutational cascade. https://doi.org/10.1099/mgen.0.000987

Ladnyj, I D., Ziegler, P., Kima, E. A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo - PubMed. (1972). https://pubmed.ncbi.nlm.nih.gov/4340218/

Loganathan, T., Fletcher, J., Abraham, P., kannangai, R., Chakraborty, C., el Allali, A., Alsamman, A. M., Zayed, H., & C, G. P. D. (2024). Expression analysis and mapping of Viral—Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox. BMC Infectious Diseases, 24(1), 1–22. https://doi.org/10.1186/S12879-024-09332-X/TABLES/7

Ramachandran, S., Kota, P., Ding, F., & Dokholyan, N. v. (2011). Automated minimization of steric clashes in protein structures. Proteins, 79(1), 261–270. https://doi.org/10.1002/PROT.22879

Vallejo-Plaza, A., Rodríguez-Cabrera, F., Sebastián, V. H., Herrador, B. R. G., Balader, P. S., Rodríguez-Alarcón, L. G. S. M., Franco, A. D., Sánchez, A. G., Moros, M. J. S., Network, S. M. R., Soria, F. S., Rodríguez, B. S., Network, S. M. R., Sánchez, E. V. M., Ruiz-Algueró, M., Simón, L., Sastre, M., Lorusso, N., Ágreda, J. P. A. P. de, … Pérez, A. C. I. (2022). Mpox (formerly monkeypox) in women: epidemiological features and clinical characteristics of mpox cases in Spain, April to November 2022. Eurosurveillance, 27(48). https://doi.org/10.2807/1560-7917.ES.2022.27.48.2200867

Wld, B., Org, H., Arita, I., & Henderson, D. A. (1968). Smallpox and monkeypox in non-human primates. Bulletin of the World Health Organization, 39(2), 277. /pmc/articles/PMC2554549/?report=abstract