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GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP).[1] The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.[1]

GTPases function as molecular switches or timers in many fundamental cellular processes.[2]

Examples of these roles include:

GTPases are active when bound to GTP and inactive when bound to GDP.[2][3] In the generalized receptor-transducer-effector signaling model of Martin Rodbell, signaling GTPases act as transducers to regulate the activity of effector proteins.[3] This inactive-active switch is due to conformational changes in the protein distinguishing these two forms, particularly of the "switch" regions that in the active state are able to make protein-protein contacts with partner proteins that alter the function of these effectors.[1]

Hydrolysis of GTP bound to an (active) G domain-GTPase leads to deactivation of the signaling/timer function of the enzyme.[2][3] The hydrolysis of the third (γ) phosphate of GTP to create guanosine diphosphate (GDP) and Pi, inorganic phosphate, occurs by the SN2 mechanism (see nucleophilic substitution) via a pentavalent transition state and is dependent on the presence of a magnesium ion Mg2+.[2][3]

GTPase activity serves as the shutoff mechanism for the signaling roles of GTPases by returning the active, GTP-bound protein to the inactive, GDP-bound state.[2][3] Most "GTPases" have functional GTPase activity, allowing them to remain active (that is, bound to GTP) only for a short time before deactivating themselves by converting bound GTP to bound GDP.[2][3] However, many GTPases also use accessory proteins named GTPase-activating proteins or GAPs to accelerate their GTPase activity. This further limits the active lifetime of signaling GTPases.[4] Some GTPases have little to no intrinsic GTPase activity, and are entirely dependent on GAP proteins for deactivation (such as the ADP-ribosylation factor or ARF family of small GTP-binding proteins that are involved in vesicle-mediated transport within cells).[5]

To become activated, GTPases must bind to GTP. Since mechanisms to convert bound GDP directly into GTP are unknown, the inactive GTPases are induced to release bound GDP by the action of distinct regulatory proteins called guanine nucleotide exchange factors or GEFs.[2][3] The nucleotide-free GTPase protein quickly rebinds GTP, which is in far excess in healthy cells over GDP, allowing the GTPase to enter the active conformation state and promote its effects on the cell.[2][3] For many GTPases, activation of GEFs is the primary control mechanism in the stimulation of the GTPase signaling functions, although GAPs also play an important role. For heterotrimeric G proteins and many small GTP-binding proteins, GEF activity is stimulated by cell surface receptors in response to signals outside the cell (for heterotrimeric G proteins, the G protein-coupled receptors are themselves GEFs, while for receptor-activated small GTPases their GEFs are distinct from cell surface receptors).

Some GTPases also bind to accessory proteins called guanine nucleotide dissociation inhibitors or GDIs that stabilize the inactive, GDP-bound state.[6]

The amount of active GTPase can be changed in several ways:

In most GTPases, the specificity for the base guanine versus other nucleotides is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. The following classification is based on shared features; some examples have mutations in the base-recognition motif that shift their substrate specificity, most commonly to ATP.[8]

The TRAFAC class of G domain proteins is named after the prototypical member, the translation factor G proteins. They play roles in translation, signal transduction, and cell motility.[8]

Multiple classical translation factor family GTPases play important roles in initiation, elongation and termination of protein biosynthesis. Sharing a similar mode of ribosome binding due to the β-EI domain following the GTPase, the most well-known members of the family are EF-1A/EF-Tu, EF-2/EF-G,[9] and class 2 release factors. Other members include EF-4 (LepA), BipA (TypA),[10] SelB (bacterial selenocysteinyl-tRNA EF-Tu paralog), Tet (tetracycline resistance by ribosomal protection),[11] and HBS1L (eukaryotic ribosome rescue protein similar to release factors).

The superfamily also includes the Bms1 family from yeast.[8]

Heterotrimeric G protein complexes are composed of three distinct protein subunits named alpha (α), beta (β) and gamma (γ) subunits.[12] The alpha subunits contain the GTP binding/GTPase domain flanked by long regulatory regions, while the beta and gamma subunits form a stable dimeric complex referred to as the beta-gamma complex.[13] When activated, a heterotrimeric G protein dissociates into activated, GTP-bound alpha subunit and separate beta-gamma subunit, each of which can perform distinct signaling roles.[2][3] The α and γ subunit are modified by lipid anchors to increase their association with the inner leaflet of the plasma membrane.[14]

Heterotrimeric G proteins act as the transducers of G protein-coupled receptors, coupling receptor activation to downstream signaling effectors and second messengers.[2][3][15] In unstimulated cells, heterotrimeric G proteins are assembled as the GDP bound, inactive trimer (Gα-GDP-Gβγ complex).[2][3] Upon receptor activation, the activated receptor intracellular domain acts as GEF to release GDP from the G protein complex and to promote binding of GTP in its place.[2][3] The GTP-bound complex undergoes an activating conformation shift that dissociates it from the receptor and also breaks the complex into its component G protein alpha and beta-gamma subunit components.[2][3] While these activated G protein subunits are now free to activate their effectors, the active receptor is likewise free to activate additional G proteins – this allows catalytic activation and amplification where one receptor may activate many G proteins.[2][3]

G protein signaling is terminated by hydrolysis of bound GTP to bound GDP.[2][3] This can occur through the intrinsic GTPase activity of the α subunit, or be accelerated by separate regulatory proteins that act as GTPase-activating proteins (GAPs), such as members of the Regulator of G protein signaling (RGS) family).[4] The speed of the hydrolysis reaction works as an internal clock limiting the length of the signal. Once Gα is returned to being GDP bound, the two parts of the heterotrimer re-associate to the original, inactive state.[2][3]

The heterotrimeric G proteins can be classified by sequence homology of the α unit and by their functional targets into four families: Gs family, Gi family, Gq family and G12 family.[12] Each of these Gα protein families contains multiple members, such that the mammals have 16 distinct α-subunit genes.[12] The Gβ and Gγ are likewise composed of many members, increasing heterotrimer structural and functional diversity.[12] Among the target molecules of the specific G proteins are the second messenger-generating enzymes adenylyl cyclase and phospholipase C, as well as various ion channels.[16]

Small GTPases function as monomers and have a molecular weight of about 21 kilodaltons that consists primarily of the GTPase domain.[17] They are also called small or monomeric guanine nucleotide-binding regulatory proteins, small or monomeric GTP-binding proteins, or small or monomeric G-proteins, and because they have significant homology with the first-identified such protein, named Ras, they are also referred to as Ras superfamily GTPases. Small GTPases generally serve as molecular switches and signal transducers for a wide variety of cellular signaling events, often involving membranes, vesicles or cytoskeleton.[18][17] According to their primary amino acid sequences and biochemical properties, the many Ras superfamily small GTPases are further divided into five subfamilies with distinct functions: Ras, Rho ("Ras-homology"), Rab, Arf and Ran.[17] While many small GTPases are activated by their GEFs in response to intracellular signals emanating from cell surface receptors (particularly growth factor receptors), regulatory GEFs for many other small GTPases are activated in response to intrinsic cell signals, not cell surface (external) signals.

This class is defined by loss of two beta-strands and additional N-terminal strands. Both namesakes of this superfamily, myosin and kinesin, have shifted to use ATP.[8]

See dynamin as a prototype for large monomeric GTPases.

Much of the SIMIBI class of GTPases is activated by dimerization.[8] Named after the signal recognition particle (SRP), MinD, and BioD, the class is involved in protein localization, chromosome partitioning, and membrane transport. Several members of this class, including MinD and Get3, has shifted in substrate specificity to become ATPases.[19]

For a discussion of Translocation factors and the role of GTP, see signal recognition particle (SRP).

While tubulin and related structural proteins also bind and hydrolyze GTP as part of their function to form intracellular tubules, these proteins utilize a distinct tubulin domain that is unrelated to the G domain used by signaling GTPases.[20]

There are also GTP-hydrolyzing proteins that use a P-loop from a superclass other than the G-domain-containg one. Examples include the NACHT proteins of its own superclass and McrB protein of the AAA+ superclass.[8]

Given line is Ax + By = C Divide by C throughout Ax/C + By/C = 1 ie, x /(C/A) + y/(C/B) = 1 This is of the form x /a + y/b = 1 which is the intercept form

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Staines Moor is one of the remaining pastures of the medieval Manor of Staines The moor has remained unploughed, no use of fertilizer or pesticides for

Main usage of Ayupan D 30mg/40mg Capsule SR is for Gastroesophageal reflux disease (Acid reflux).

Ayupan D 30mg/40mg Capsule SR

Gastroesophageal reflux disease (GERD) is a chronic (long-term) condition in which there is an excess production of acid in the stomach. Ayupan D 30mg/40mg Capsule SR reduces the amount of acid your stomach makes and relieves the pain associated with heartburn and acid reflux. You should take it exactly as it is prescribed for it to be effective. Some simple lifestyle changes can help reduce the symptoms of GERD. Think about what foods trigger heartburn and try to avoid them; eat smaller, more frequent meals; try to lose weight if you are overweight and try to find ways to relax. Do not eat within 3-4 hours of going to bed.

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In my experience, using if-else statements are not a good practice. It makes the code less readable and it makes developers lazy in thinking of better ways of making their code more readable.

For the few examples given in this article, I used TypeSript. For those who are not familiar with TypeSript yet, it is a superset of JavaScript, in other words, it is also a strongly-typed JavaScript hence the name TypeScript. You can still follow the examples in the Programming Language that you prefer. FYI, I choose TypeScript for this example because of its strongly-typed syntax so that when we read the code, we know what type is what.

In my experience these are the two common use cases of using else-if statements are:

One of our use cases for if-else statements is when we are trying to resolve a value. For instance, this example:

Disclaimer: It is better to use a switch statement but for the sake of demonstrating how we can write better if-else statements, we’re going to do it using if-else statements

In this example, what the code does is resolve the value of the name variable based on the current value of the gender variable. There is nothing really wrong about coding it this way. Technically you will still be able to accomplish your desired output, but there are better ways in re-writing this into a much readable code.

Now, the code becomes more clear compared to the first one. We now have refactored the code, thus coming up with function called getName. This function has a parameter name of gender. Look closely on what the function is doing. If the gender is “male” then the function will immediately return “Robert”. If the gender is “female” then the function will immediately return “Margot”. If the gender is not “male” nor “female” then the function will return an empty String. By writing it this way, we can now be able to read or grasp a much better perspective of what the code does. It is also much easier to follow since we are utilizing the power of the return statement.

We use if-else statements in implementing validations. If we have complex validations we may resolve in using else-if statements, right? No, we should try and look for alternatives first.

In this continuation, I created a function isGenderValid that takes a parameter name of gender. This function returns a boolean in which we can use as our indicator in our logic whether the gender is valid or not. In this implementation of the function isGenderValid, we can immediately see that if the gender is a falsy, our function immediately returns a boolean value of false. Then if the gender parameter is not equal to “male” and is not equal to “female” then we can also return false. Otherwise, we can return true. What we did was we first coded all the criteria of the function isGenderValid where it will return false before finally returning a value of true.

Compare it when we try to use an if-else statement that is nested and that does not utilize the power of the return statement, We get this (Code 1.4). Right now it is a bit readable but imagine implementing in style and reading hundreds if not thousands of lines of code with multiple nested if-else statements that have only one return statement. You will be easily confused when the function is returning a value or when a function finishes its execution unlike our first example (Code 1.3) above.

The take-home of this article is to widen our use case of the if-else statement without sacrificing code readability. Other takeaways are to Compartmentalize our code. Have our functions/methods do only one thing. Always prevent yourself from writing nested if-else statements. By keeping this to mind, we will be more effective in writing good, testable codes, and we will be a more productive member of the team we are in.