G PROTEINS: STRUCTURE, TYPES AND FUNCTIONS - BIOLOGY - 2025

The G proteins, or guanine nucleotide binding proteins, are proteins associated with the plasma membrane belonging to a family of signal "coupler" proteins that have important functions in many signal transduction processes in eukaryotic organisms.

In the literature, G proteins are described as binary molecular switches, since their biological activity is determined by the changes in their structure given by the nucleotide species to which they are able to bind: guanosine nucleotides (diphosphate (GDP) and triphosphate (GTP)).

Structure of the Ras protein, a monomeric G protein (Source: Mark 'AbsturZ' via Wikimedia Commons)

They are generally activated by receptors of a family of proteins known as G-protein-coupled receptors (GPCR), which receive an external initial signal and convert it into conformational changes that trigger activation, which it is subsequently translated into the activation of another effector protein.

Some authors consider that the coding genes for this family of proteins evolved by duplication and divergence of a common ancestral gene, whose product was refined and specialized more and more.

Among the great variety of cellular functions that these proteins have are the translocation of macromolecules during protein synthesis, the transduction of hormonal signals and sensory stimuli, as well as the regulation of cell proliferation and differentiation.

Two classes of this type of protein have been described: the small G proteins and the heterotrimeric G proteins. The first three-dimensional structure of a G protein was derived more than a decade ago from a small G protein known as Ras.

Structure

Structurally speaking, two types of G proteins are recognized: the small G proteins and the much more complex heterotrimeric G proteins.

Small G proteins are made up of a single polypeptide of about 200 amino acid residues and about 20-40 kDa, and in their structure there is a conserved catalytic domain (the G domain) composed of five α-helices, six β-folded sheets, and five polypeptide loops.

Heterotrimeric G proteins, on the other hand, are integral membrane proteins that are composed of three polypeptide chains, known as the α, β, and γ subunits.

-The α subunit weighs between 40 and 52 kDa, has a guanine nucleotide binding region and has GTPase activity to hydrolyze bonds between the phosphate groups of GTP.

The α subunits of different G proteins share some structural domains such as those for binding and hydrolysis of GTP, but they are very different in the binding sites for receptor and effector proteins.

-The β subunit has a slightly lower molecular weight (between 35 and 36 kDa).

-The γ subunit, on the other hand, is much smaller and has an approximate molecular weight of 8 kDa.

All heterotrimeric G proteins have 7 transmembrane domains and share sequence similarity to the β and γ domains. These two domains are so strongly associated that they are viewed as a single functional unit.

Types

As mentioned above, there are two types of G proteins: small and heterotrimeric.

Small G proteins have roles in cell growth, protein secretion, and intracellular vesicle interaction. On the other hand, heterotrimeric G proteins are associated with the transduction of signals from surface receptors, and also act as switches that alternate between two states depending on the associated nucleotide.

Small G proteins

These proteins are also called small GTPases, small GTP-binding proteins, or Ras protein superfamily and form a separate superfamily within the large class of GTP hydrolases with regulatory functions.

These proteins are very diverse and control multiple cellular processes. They are characterized by a conserved GTP-binding domain, the "G" domain. The binding of this phosphate nucleotide causes important conformational changes in their catalytic domain in small G proteins.

Its activity is closely related to GTPase Activating Protein (GAP) and Guanine Nucleotide Exchange Factor (GEF).

Five classes or families of small G proteins have been described in eukaryotes:

-Ras

-Rho

-Rab

-Sar1 / Arf

-Ran

The Ras and Rho proteins control gene expression and the Rho proteins also modulate the reorganization of the cytoskeleton. The Rab and Sar1 / Arf group proteins influence vesicular transport and the Ran proteins regulate nuclear transport and the cell cycle.

Heterotrimeric G proteins

This type of protein also deserves an association with two other protein factors, so that the signaling pathway from the external environment to the interior of the cell is made up of three elements in the following order:

1. The receptors coupled to G proteins
2. The G proteins
3. The proteins or channels effectors

There is a great diversity of heterotrimeric G proteins and this is related to the great diversity of α subunits that exist in nature, in which only 20% of the amino acid sequence is conserved.

Heterotrimeric G proteins are usually identified thanks to the diversity of the α subunit, based mainly on their functional and sequence similarities.

The α subunits are made up of four families (the Gs family, the Gi / o family, the Gq family and the G12 family). Each family is made up of a different “isotype” that together add up to more than 15 different forms of α subunits.

G family

This family contains representatives that also participate in the up-regulation of adenylate cyclase proteins and is expressed in most cell types. It is made up of two members: Gs and Golf.

The subscript “s” refers to stimulation and the subscript “olf” refers to “smell” (from English “olfaction”). Golf proteins are especially expressed in the sensory neurons responsible for smell.

G family

This is the largest and most diverse family. They are expressed in many cell types and mediate receptor-dependent inhibition of various types of adenyl cyclase (the subscript "i" refers to inhibition).

Proteins with the α subunits of the Go group are expressed especially in cells of the central nervous system and have two variants: A and B.

G family

Proteins with this α-subunit family are responsible for the regulation of phospholipase C. This family consists of four members whose α-subunits are expressed by different genes. They are abundant in liver cells, kidney cells, and lungs.

G family

This family is ubiquitously expressed in organisms and it is not known with certainty what exactly are the cellular processes regulated through proteins with these subunits.

Β and γ subunits

Although the diversity of alpha structures is decisive for the identification of heterotrimeric proteins, there is also a lot of diversity with respect to the other two subunits: beta and gamma.

Features

G proteins participate in the "channeling" of signals from receptors on the plasma membrane to effector channels or enzymes.

The most common example of the function of this type of protein is in the regulation of the enzyme adenylate cyclase, an enzyme responsible for the synthesis of adenosine 3 ', 5'-monophosphate or simply cyclic AMP, a molecule that has important functions as a second messenger in many known cellular processes:

-Selective phosphorylation of proteins with specific functions

-Genetic transcription

-Reorganization of the cytoskeleton

-Secretion

-Depolarization of the membrane

They also indirectly participate in the regulation of the signaling cascade of inositols (phosphatidylinositol and its phosphorylated derivatives), which are responsible for the control of calcium-dependent processes such as chemotaxis and the secretion of soluble factors.

Many ion channels and transport proteins are directly controlled by proteins of the G protein family. Likewise, these proteins are involved in many sensory processes such as vision, smell, among others.

How do they work?

The mode of interaction of a G protein with effector proteins is specific to each class or family of proteins.

For G proteins coupled with membrane receptors (heterotrimeric G proteins), the binding of a guanine nucleotide such as GDP or guanosine diphosphate to the α subunit causes the association of the three subunits, forming a complex known as Gαβγ or G-GDP, which is attached to the membrane.

If the GDP molecule is subsequently exchanged for a GTP molecule, the α subunit bound to GTP dissociates from the β and γ subunits, forming a separate complex known as Gα-GTP, which is capable of altering the activity of its enzymes or target carrier proteins.

The hydrolytic activity of this subunit allows it to finish the activation, exchanging the GTP for a new GDP, passing to the inactive conformation.

In the absence of the excited receptors that associate with G proteins, this process of exchange from GDP to GTP is very slow, which means that heterotrimeric G proteins only exchange GDP for GTP at a physiologically significant rate when they are bound to their excited receptors.

References

1. Gilman, G. (1987). G Proteins: Transducers of Receptor-Generated Signals. Annual Reviews in Biochemistry, 56, 615-649.
2. Milligan, G., & Kostenis, E. (2006). Heterotrimeric G-proteins: a short history. British Journal of Pharmacology, 147, 546–555.
3. Offermanns, S. (2003). G-proteins as transducers in transmembrane signaling. Progress in Biophysics & Molecular Biology, 83, 101–130.
4. Simon, M., Strathmann, MP, & Gautam, N. (1991). Diversity of G Proteins in Signal Transduction. Science, 252, 802-808.
5. Syrovatkina, V., Alegre, KO, Dey, R., & Huang, X. (2016). Regulation, Signaling, and Physiological Functions of G-Proteins. Journal of Molecular Biology, 428 (19), 3850–3868.