In molecular biology, the guanylate-binding proteins

family Family (from ) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). It forms the basis for social order. Ideally, families offer predictabili ...

is a family of

GTPases 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 pro ...

that is induced by interferon (IFN)-gamma. GTPases induced by IFN-gamma ( Interferon-inducible GTPase) are key to the protective

immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...

against

microbial A microorganism, or microbe, is an organism of microscopic size, which may exist in its single-celled form or as a colony of cells. The possible existence of unseen microbial life was suspected from antiquity, with an early attestation in ...

and viral

pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...

s. These GTPases are classified into three groups: the small 47-KD immunity-related GTPases ( IRGs), the Mx proteins ( MX1, MX2), and the large 65- to 67-kd GTPases. Guanylate-binding

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s (GBP) fall into the last class.

Genetic Information

GBP genes have been universally recognized in mammalian as well as in most other vertebrate genomes. A single cluster of seven human GBP genes (GBP1-GBP7) is found on chromosome 1q22.2. Unlike humans, in genetically controllable disease models such as mice and zebrafish, members of the GBPs gene family are organized in more than one cluster, in this case, 11 (Gbp2b- Gbp110 and 4 genes (Gbp1-Gbp4), respectively. Examinations of GBP-related sequences have shown that zebrafish gbp3 and gbp4 contain an additional function to find ( FIIND) and a caspase recruitment (

CARD Card or The Card may refer to: Common uses * Plastic cards of various types: **Bank card **Credit card **Debit card **Payment card * Playing card, used in games * Printed circuit board, or card * Greeting card, given on special occasions Arts an ...

) domains that resemble those found within the inflammasome-related proteins: Apoptosis-associated speck-like protein containing a CARD (

PYCARD PYCARD, often referred to as ASC (Apoptosis-associated speck-like protein containing a CARD), is a protein that in humans is encoded by the ''PYCARD'' gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen ...

) and NLR Family Pyrin Domain Containing 1 (

NLRP1 NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution ...

Structure

Structurally, GBPs consist of two domains: a globular N- terminal domain harboring the

GTPase 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 ...

function, and an extended C- terminal helical domain. In addition, some members of the GBPs family harbor motifs (e.g., CaaX motifs) or additional domains that are thought to operate in protein-protein or protein-membrane interactions.

Activity

Some GBPs have exhibited the ability to bind not only

guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only di ...

(GTP) to produce

guanosine diphosphate 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. GDP is the pr ...

(GDP) but also GDP to produce

guanosine monophosphate Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid (conjugate base guanylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the p ...

(GMP) with equimolar affinity and high intrinsic rates of hydrolyzation. The physiological

relevance Relevance is the connection between topics that makes one useful for dealing with the other. Relevance is studied in many different fields, including cognitive science, logic, and library and information science. Epistemology studies it in gener ...

of the GBP's GDPase activity might yield important insights to elucidate GBP-specific defensive profile versus other INF-induced GTPases(e.g. IRGs). Evidence has suggested GBPs as important players in a variety of disease conditions ranging from

infectious infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

and

metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

inflammatory

diseases A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are asso ...

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, In the context of cell protection against bacteria, early efforts conducting loss-function assays revealed a reduced host resistance to several pathogens when lacking GBPs. More recent studies have indicated that GBPs appear to be an agent that disturbs the structural integrity of bacteria, stimulates

inflammasome Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sens ...

signaling, forms complexes on pathogen-containing vesicles in infected cells, and fosters

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

and oxidative mechanisms helping

clearance.

Human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

GBP1 is

secreted Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mech ...

from

cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...

without the need of a leader peptide, and has been shown to exhibit antiviral activity against

Vesicular stomatitis virus ''Indiana vesiculovirus'', formerly ''Vesicular stomatitis Indiana virus'' (VSIV or VSV) is a virus in the family ''Rhabdoviridae''; the well-known '' Rabies lyssavirus'' belongs to the same family. VSIV can infect insects, cattle, horses and pig ...

and Encephalomyocarditis virus, as well as being able to regulate the inhibition of proliferation and invasion of

endothelial cell The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...

s in response to IFN-gamma.

GBP1 Interferon-induced guanylate-binding protein 1 is a protein that in humans is encoded by the ''GBP1'' gene. It belongs to the dynamin superfamily of large GTPases. Function Guanylate binding protein expression is induced by interferon ...

, the most widely studied GBP, has been studied for its antimicrobial properties. It can effectively polymerize and target the lipopolysaccharide cell wall of

gram-negative bacteria Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelo ...

. In said bacteria type, the GBP1 polymer coating alters the lipopolysaccharide membrane, allowing access to other parts of the membrane by other innate antimicrobial agents within the cell to cause pathogen cell death. Besides detecting pathogens and causing bacterial cell lysis, GBP1 can also cause host-programmed cell death. The GBP family of proteins is highly conserved among many different phyla. They are believed to be a shared gene family that is used to fight off mostly viral, parasitic, and bacterial infections. On that note, the expression of GBPs is noted to increase in humans once the body detects many different types of diseases ranging from the infections listed above to cancer. Due to the similarity between murine and human GBPs, mouse knockout studies have been utilized to investigate the different roles GBPs have in fighting off other diseases. These studies have confirmed that knocking out different GBPs has different effects on combating different infections.

References

{{InterPro content, IPR015894 Protein domains