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Draft: Actin Depolymerizing Factor

Actin Depolymerizing factor is a family of proteins involved in the depolymerizing of actin polymers. This family includes cofilin/ADF, Cofilin-1, and Cofilin-2. [6]

Structure

The structure of Actin depolymerizing factor is highly evolutionarily conserved.[5] Proteins of the actin depolymerizing factor family consist of 5 beta sheets, 4 antiparallel and 1 parallel, and 4 alpha helices with a central alpha helix providing the characteristic structure of the proteins.[7] Regions important actin binding include the central alpha helix, the N terminus extension and the C terminus helix. [8] The tilted loop at the N terminus extension enables it to bind G-actin but not F-actin. [7] The C terminus can form hydrogen bonds to F actin through its amide backbone as well as S274, a highly evolutionarily conserved Serine due to its importance in actin binding. [8]

Mechanism of Action

Actin Depolymerization factors bind to F-actin subunits and twist these subunits, causing destabilization of the actin polymer and catalyzes depolymerization [4]. This destabilization is caused by the binding of the actin depolymerizing factor leading to the F-actin being unable to bind phailoid which is necessary for the structural stability of the actin polymer. [4] This is due to the binding of actin depolymerization factor being cooperative and causing a conformational change in the phaloid binding site in F-actin which inhibits it from binding. [4]

F-actin is bound to ATP, but when it is bound to actin depolymerizing factor, its hydrolyzes ATP to ADP and releases inorganic phosphate. [5] This release of inorganic phosphate further destabilizes the actin polymer, and cofilin binds the released phosphate. [5]

Regulation

Tropomyosin bound to F site of actin blocking ADF/cofilin

Actin depolymerization is highly regulated by many factors within the cell.

pH changes

A higher pH is associated with an increased concentration of actin depolymerizing factor. [4] An alkaline environment stabilizes the free inorganic phosphate, so therefore the hydrolyzation of ATP to ADP and the release of the inorganic phosphate becomes more favorable in low pH.

Activation of Actin Depolymerizing Factor

Actin depolymerizing factor is activated by the dephosphorylation of a conserved serine, and is in its inactive state when that serine is phosphorylated. [5]

Feedback (by Manvita Mareboina)

·       I really liked the topic and found it very interesting. My number one comment would be to add more information to make the article more specific and clearer on the topic.

·       Including the main purpose of the Actin Depolymerizing factor in the first intro paragraph would be very helpful to understand what it is from the very beginning. However, the structure of going from intro to structure to action and regulation was very nice.

·       Maybe describing in the structure how the central helix and stability aid in its function will connect the mechanism and structure section better.

·       Although it is stated what the family of this factor includes, it is hard for the reader to know what that means so listing what those molecules such as ADF and Cofilin-1 are may be more helpful.

·       Under regulation, the sentence is very vague in saying that it is “regulated by many factors within the cell.” Perhaps expanding on what these factors are or how they regulate actin depolymerization specifically will help give the reader a clearer understanding. Include information on what the conserved serine is and how dephosphorylation and phosphorylation work to activate and inactivate the factor.

·       There is no information that is redundant, however information should be added to specify key words in each subsection.

·       Overall the organization is good, there is no bias and the topic is interesting but adding more information will make this a better article. Having more references will really help with adding more information. Everything written is good and unbiased, but having more information that gets into the specifics of each subsection (including more forms of regulation) would be very helpful.

Outline

A. Actin Depolymerizing factor is a family of proteins involved in the depolymerization of actin polymers

1. Consist of Cofilins and ADF

B. Mechanism of action [4]

2. Cofilins/ADF binds to F-actin subunits and twists them

3. this twisting makes F actin unable to bind phailloidin, which is necessary for structural stability. this destabilizes actin filaments

4. Binding of ADF is cooperative and induces conformational change

5. ATP bound F Actin hydrolyzes ATP to ADP and Pi [5] Picture of F-actin binding site [3]

a. release of Pi destabilizes actin, cofilin binds released Pi

C. Regulation

1. Regulated by capped ends of short actin filaments
   1. stop actin depolymerizing factors from binding to F sites

2. Competitive binding with Tropomyosin [4]

a. Tropomyosin binds actin uncooperatively (does not induce conformational change)

b. when actin is bound to tropomyosin it cannot bind ADF

3. PH changes [4]

a. Ph increases are also increase concentration of ADF present, and increases rate of actin depolymerization

b. Alkaline environment promotes weaker Pi binding to actin so Pi is more likely to be release which destabilizes actin [5]

4. Phosphorylation

a. Phosphorylation of Serine leads to deactivation of ADF, dephosphorylation activates ADF

Sources:

1. doi: 10.1007/s10265-016-0899-8 mechanism of action of ADF
2. doi: 10.1242/jcs.187849 intracellular regulation of actin depolymerizing factors
3. doi:  10.1146/annurev-biophys-042910-155359 structure and function of actin
4. https://doi.org/10.1016/S0962-8924(99)01619-0 structure of actin depolymerizing factor
5. https://www.mechanobio.info/cytoskeleton-dynamics/what-is-the-cytoskeleton/what-are-actin-filaments/how-do-actin-filaments-depolymerize/ More layman friendly mechanism of actin depolymerization mechanism, might need to visit cited articles to get more information but good overview.
6. https://doi.org/10.1016/bs.ircmb.2015.10.002
7. doi: 10.1002/pro.248

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2,3-BPG and beefy meaty peptide may not have enough content to add to the page. What were you planning for either of those pages? The other three, particularly actin depolymerizing factor look good. - D. Tienson-Tseng