Arginine finger

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In molecular biology, an arginine finger is an amino acid residue of some enzymes. [1] [2] Arginine fingers are often found in the protein superfamily of AAA+ ATPases, GTPases, and dUTPases, where they assist in the catalysis of the gamma phosphate or gamma and beta phosphates from ATP or GTP, which creates a release of energy which can be used to perform cellular work. [3] [1] [4] [2] They are also found in GTPase-activating proteins (GAP). [5] Thus, they are essential for many forms of life, and are highly conserved. [3] [1] [6] Arginine fingers function through non-covalent interactions. [1] They may also assist in dimerization, and while they are found in a wide variety of enzymes, they are not ubiquitous. [7] [8]

Contents

Role in catalytic mechanisms

Generally, the role of the arginine finger in catalysis is to function in transition state stabilization to allow water to perform a nucleophilic attack to cleave off a number of phosphate groups. [1] [8] However, there are exceptions, and arginine fingers can assist in other roles. [9] [7] Additionally, arginine fingers may be attached to different subunits or other proteins in a multiprotein complex. [8] Arginine fingers sometimes interact with guanidinium during their role in catalysis. [10] [8]

dUTPases

Arginine fingers often work with other features in their assistance of catalysis. [1] For example, in some trimeric dUTPases, such as those of M. tuberculosis, arginine fingers at the 64th and 140th residue can work with magnesium to cleave dUTP into dUMP and a pyrophosphate. [1] [11] The underlying mechanism of action for this is a nucleophilic attack; the positively charged magnesium ion (Mg2+
) pulls on an oxygen of the beta and gamma phosphates to allow water to hydrolyze the bond between the beta and alpha phosphates. [1] The arginine fingers help stabilize the transition state. [1] Arginine fingers often interact with other motifs such as the Walker motifs and to perform catalysis more efficiently. [4] [7] [2]

Ras GTPases

Arginine fingers are also present in Ras GTPases, where they help cleave GTP to turn Ras off. [12] [6] Ras is a GTPase which functions in signal transduction to regulate cell growth and division. [13] [14] In addition to being positively charged, which helps arginine fingers function as a catalyst, the arginine finger in Ras displaces solvent molecules and creates an optional charge distribution. [9] [14] [15] Like those of dUPTases, the arginine fingers of Ras GTPases are assisted by a magnesium ion. [15] Furthermore, multiple arginine finger residues can all point towards the same point, thus focusing their effect. [16] Mutations affecting the arginine fingers of Ras lead to trouble catalyzing GTP by factors of around two to five orders of magnitude. [9] [6] [4] [15] Thus, as Ras is an oncogene and is activated and deactivated by the hydrolysis of GTP, mutations in Ras's arginine finger residues can lead to cancer. [6] [3] Glutamate also plays a role near arginine fingers and is stabilized by the arginines' backbone chain carboxyl groups, which are known as knuckles. [16]

Heterotrimeric G proteins

In heterotrimeric G proteins, catalysis of GTP can be assisted by aluminum tetrafluoride (AlF
4) and RGS4. [16] [3] Heterotrimeric G proteins are larger three-part proteins serve in signal transduction of many pathways. [3] The catalytic mechanism for GTP hydrolysis in heterotrimeric G proteins consists of an active state where catalysis is likely to occur and an inactive state where catalysis is unlikely. [3] In the active state, AlF
4 stabilizes the transition state and points the arginine finger residue towards GTP. [3] This causes increased charge density on the beta phosphate of GTP and planarization of the gamma phosphate, which creates an opening and reduces steric hindrance for water to hydrolyze the phosphoanhydride beta-gamma bond. [3] This is because the gamma phosphate's bond to the beta phosphate bends, exposing its connection and allowing the subsequent nucleophilic substitution reaction initiated by water. [3] The complex formed with RGS4 assists in this process by creating strain on the bond between the gamma and beta phosphates and assisting in distributing more charge onto the beta phosphate. [3]

ATP synthase

ATP synthase consists of a F1 and F0 subunit. [10] The F1 subunit contains alpha and beta subunits of its own which can assist in the formation of ATP, or hydrolyze it to serve as a proton pump. [17] Though most catalytic actions happen on the beta subunits, the alpha subunits each contain an arginine finger. [10] The role of the arginine finger in ATP synthase is akin to the function of the arginine finger residues of G proteins; to help split ATP. [10] For example, if the arginine of the arginine finger is substituted by lysine, possibly due to a missense mutation, the αR364K mutant results. [10] In the αR364K mutant, the ability of ATP synthase to hydrolyze ATP is decreased around a thousandfold compared to the wild type. [10]

RecQ helicase

A RecQ helicase is one of a family of helicases that helps reduce sister chromatid exchange during meiosis to lower mutation rates. [18] [8] RecQ helicases are found in many organisms, ranging from E. coli to humans. [18] [8] One of these helicases, the Bloom syndrome protein, contains an arginine finger which assists in its hydrolysis of ATP. [8] In humans, the arginine finger of the Bloom syndrome protein is Arg982. [8] The RecQ helicase, along with most proteins containing arginine fingers, is inhibited by sodium orthovanadate, which interferes with the arginine finger residue. [8]

Related Research Articles

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

<span class="mw-page-title-main">G protein</span> Type of proteins

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

<span class="mw-page-title-main">ATPase</span> Dephosphorylation enzyme

ATPases (EC 3.6.1.3, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or the inverse reaction. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.

<span class="mw-page-title-main">ATP synthase</span> Enzyme

ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed by ATP synthase is:

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Ras GTPase</span> GTP-binding proteins functioning on cell-cycle regulation

Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.

Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

<span class="mw-page-title-main">Guanosine diphosphate</span> Chemical compound

Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine.

<span class="mw-page-title-main">ADP ribosylation factor</span> Group of proteins

ADP ribosylation factors (ARFs) are members of the ARF family of GTP-binding proteins of the Ras superfamily. ARF family proteins are ubiquitous in eukaryotic cells, and six highly conserved members of the family have been identified in mammalian cells. Although ARFs are soluble, they generally associate with membranes because of N-terminus myristoylation. They function as regulators of vesicular traffic and actin remodelling.

<span class="mw-page-title-main">Heterotrimeric G protein</span> Class of enzymes

Heterotrimeric G protein, also sometimes referred to as the "large" G proteins are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors, directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.

G12/G13 alpha subunits are alpha subunits of heterotrimeric G proteins that link cell surface G protein-coupled receptors primarily to guanine nucleotide exchange factors for the Rho small GTPases to regulate the actin cytoskeleton. Together, these two proteins comprise one of the four classes of G protein alpha subunits. G protein alpha subunits bind to guanine nucleotides and function in a regulatory cycle, and are active when bound to GTP but inactive and associated with the G beta-gamma complex when bound to GDP. G12/G13 are not targets of pertussis toxin or cholera toxin, as are other classes of G protein alpha subunits.

<span class="mw-page-title-main">G alpha subunit</span>

G alpha subunits are one of the three types of subunit of guanine nucleotide binding proteins, which are membrane-associated, heterotrimeric G proteins.

<span class="mw-page-title-main">Regulator of G protein signaling</span>

Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.

<span class="mw-page-title-main">ATP synthase alpha/beta subunits</span>

The alpha and beta subunits are found in the F1, V1, and A1 complexes of F-, V- and A-ATPases, respectively, as well as flagellar (T3SS) ATPase and the termination factor Rho. The subunits make up a ring that contains the ATP-hydrolyzing catalytic core. The F-ATPases, V-ATPases and A-ATPases are composed of two linked complexes: the F1, V1 or A1 complex containsthat synthesizes/hydrolyses ATP, and the Fo, Vo or Ao complex that forms the membrane-spanning pore. The F-, V- and A-ATPases all contain rotary motors, one that drives proton translocation across the membrane and one that drives ATP synthesis/hydrolysis.

<span class="mw-page-title-main">ATP5C1</span> Protein-coding gene in the species Homo sapiens

The human ATP5F1C gene encodes the gamma subunit of an enzyme called mitochondrial ATP synthase.

<span class="mw-page-title-main">ATP5E</span> Protein-coding gene in the species Homo sapiens

ATP synthase F1 subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5F1E gene. The protein encoded by ATP5F1E is a subunit of ATP synthase, also known as Complex V. Variations of this gene have been associated with mitochondrial complex V deficiency, nuclear 3 (MC5DN3) and Papillary Thyroid Cancer.

<span class="mw-page-title-main">GNA12</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein subunit alpha-12 is a protein that in humans is encoded by the GNA12 gene.

The Walker A and Walker B motifs are protein sequence motifs, known to have highly conserved three-dimensional structures. These were first reported in ATP-binding proteins by Walker and co-workers in 1982.

<span class="mw-page-title-main">GoLoco motif</span> Protein structural motif

GoLoco motif is a protein structural motif. In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolyzing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to the receptor, GDP is displaced from G-alpha and GTP is bound. The GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP-bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis, and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators. acts as a GDI on G-alpha(i).

<span class="mw-page-title-main">Protein–ligand complex</span>

A protein–ligand complex is a complex of a protein bound with a ligand that is formed following molecular recognition between proteins that interact with each other or with other molecules. Formation of a protein-ligand complex is based on molecular recognition between biological macromolecules and ligands, where ligand means any molecule that binds the protein with high affinity and specificity. Molecular recognition is not a process by itself since it is part of a functionally important mechanism involving the essential elements of life like in self-replication, metabolism, and information processing. For example DNA-replication depends on recognition and binding of DNA double helix by helicase, DNA single strand by DNA-polymerase and DNA segments by ligase. Molecular recognition depends on affinity and specificity. Specificity means that proteins distinguish the highly specific binding partner from less specific partners and affinity allows the specific partner with high affinity to remain bound even if there are high concentrations of less specific partners with lower affinity.

References

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