Forkhead-associated domain containing protein 1 (FHAD1) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

encoded by the FHAD1

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. As the name suggests, it has a

forkhead-associated domain In molecular biology, the forkhead-associated domain (FHA domain) is a phosphopeptide recognition domain found in many regulatory proteins. It displays specificity for phosphothreonine-containing epitopes but will also recognise phosphotyrosine wi ...

and an extensive

coiled coil A coiled coil is a structural motif in proteins in which 2–7 alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fun ...

structure. It is predicted to have a function related to

DNA transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...

. It is localized to the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

and has a

nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...

Gene

Locus and Size

humans Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...

, the FHAD1 gene is located on

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

1 (1p36.21) and the genomic sequence is on the plus strand starting from 15236559 bp and ending at 15400283 bp. There are 3 main genes around FHAD1, out of which 2 encode proteins with known functions. Two genes, EFHD2 and Chymotrypsin-C (CTRC) lie downstream of FHAD1 on the plus strand. TMEM51 lies upstream of FHAD1. FHAD1 is 163,682 bases long and contains 43

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

Common Aliases

FHAD1 has 4

aliases A pseudonym (; ) or alias () is a fictitious name that a person or group assumes for a particular purpose, which differs from their original or true name ( orthonym). This also differs from a new name that entirely or legally replaces an individu ...

, Forkhead associated

phosphopeptide Phosphopeptides are modified self antigens which may induce an immune response. Protein phosphorylation is a very important and frequent post-translational modification that can impact a protein's localization, stability, and whether or not it c ...

binding domain 1, Forkhead-associated (FHA) phosphopeptide binding domain 1, FHA Domain-Containing Protein 1, and KIAA1937.

mRNA

The

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

transcript of FHAD1 5138 bp long. The gene has 30

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

based on NCBI gene data.

Protein

The FHAD 1 protein is 1412 aa long, weighs 16.2 kDa and has an

isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). However, pI is also u ...

of 6.52. It has 3 isoforms, namely 1, 3 and 4, but only isoform 1 is supported by experimental evidence. It consists of 1

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

rich region and 1

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

rich region.

Domains and Motifs

Forehead-associated domain

The FHA domain extends from 18 - 84 aa in the protein. It can recognize and bind to

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

sites, specifically pSer, pThr and pTyr. The exact mechanism and function of this domain still being studied, but it is found in proteins performing many different functions, mainly

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

and transduction. FHA_domain

Smc region

FHAD1 contains one Smc (Structural maintenance of chromosomes) region from 275 - 1401 aa. This region encodes Smc proteins that are involved in cell cycle control, cell division and chromosome separation.

TMPIT-like protein, pfam07851

This region extends from 394 - 494 aa in FHAD1. The proteins encoded by the TMPIT proteins are predicted to be

transmembrane proteins A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

. However, there is lack of literature to support this.

DUF342

This domain extends from 694 - 777 aa in FHAD1. It encodes a protein from a family of

bacterial Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

proteins with no known function. Secondary_structure_of_FHAD1

Structure

FHAD1 contains the forkhead-associated domain that consists of

beta sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

. Based on structure prediction softwares, the rest of the protein consists of

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

and random coils. Overall, FHAD1 has a coiled coil structure as shown in the figure.

Post-translational modifications

FHAD1 is predicted to undergo multiple different types of post-translational modifications based on prediction softwares. *

Glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...

: There were 101 possible glycosylation sites on FHAD1 and consisted mainly of amino acids involved in O-linked glycosyaltion. * Phosphorylation: The protein was predicted to have a large number of phosphorylation sites, at least more than 100. *

Glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proces ...

: Multiple lysine residues of FHAD1 were predicted for glycation of their ε amino groups. *

SUMOylation In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...

: 4 SUMOylation consensus sequences and 3 interaction sites were predicted on FHAD1. * O-GlcNAc sites: 6 sites for O-GlcNAc glycosylation were predicted on FHAD1. Research has shown that this specific type of glycosylation is most abundant in nucleocytoplasmic proteins.

Subcellular localization

FHAD1 has been predicted to be a

nuclear protein A nuclear protein is a protein found in the cell nucleus. Proteins are transported inside the nucleus with the help of the nuclear pore complex, which acts a barrier between cytoplasm and nuclear membrane. The import and export of proteins through ...

with 94.1% reliability. It also contains possible nuclear localization signal sequences between 1100 - 1107 aa. Two pat4 and one pat7 sequences were predicted. Pat4 and pat7 are consensus sequences consisting of clusters of

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

residues.

Expression

In humans, FHAD1 is expressed in

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...

fallopian tube The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ot ...

and

uterine The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the hollow organ, organ in the female reproductive system, reproductive system of most female mammals, including humans that accommodates the embryonic development, embryonic an ...

tissues in

females Female (symbol: ♀) is the sex of an organism that produces the large non-motile ova (egg cells), the type of gamete (sex cell) that fuses with the male gamete during sexual reproduction. A female has larger gametes than a male. Females a ...

nasopharynx The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its struct ...

and

bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...

lungs The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...

based on studies found on the Human Protein Atlas. NCBI's EST Profile also showed that FHAD1 is highly expressed in the testis, with some expression in the

trachea The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...

and

esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...

. In

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, the gene was also expressed in the testis, along with the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

and

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

Regulation of expression

FHAD1 has a promoter that extends from 15246234 – 15247380 bp and is 1147 bp long. It includes an initial part of the 5' UTR of FHAD1. Some transcription factors predicted to bind to this promoter are: * MAX binding protein - This protein is likely a transcriptional

repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...

from the

E-box An E-box (enhancer box) is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG (where N can b ...

binding factors family * TR4/TR2 - These proteins are part of a family of

nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of specif ...

and bind to DR1 (direct repeat) elements of promoters. They act as anchors to recruit other corepressors 5' UTR stem loop structure

Kaiso Kaiso is a type of music popular in Trinidad and Tobago, and other countries, especially of the Caribbean, such as Grenada, Belize, Barbados, St. Lucia and Dominica, which originated in West Africa particularly among the Efik and Ibibio peop ...

- This transcriptional regulator is encoded by the

ZBTB33 Transcriptional regulator Kaiso is a protein that in humans is encoded by the ''ZBTB33'' gene. This gene encodes a transcriptional regulator with bimodal DNA-binding specificity, which binds to methylated CGCG and also to the non-methylated consen ...

gene and is involved in response to

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

by interacting with

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

LYL1 Protein lyl-1 is a protein that in humans is encoded by the ''LYL1'' gene. Interactions LYL1 has been shown to interact with TCF3 and NFKB1 Nuclear factor NF-kappa-B p105 subunit is a protein that in humans is encoded by the ''NFKB1'' gene. ...

- E12 - This transcriptional factor is a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...

of two proteins, LYL1 and E12, where E12 is an E-box binding protein. LYL1 is also involved in some

leukemias Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and is a possible

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

factor. * Nur 77 - This protein is also known as NGFIB (Nerve growth factor IB) and belongs to a family of nuclear receptors. It is involved in

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and

cell growth Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...

pathways.

In the 5' UTR and 3' UTR of FHAD1, multiple stem loops are predicted to form .

Function

FHAD1 can be involved in transcriptional regulation through interaction with other transcriptional regulators.

Protein interactions

FHAD1 was found to be a binding partner for

GTF2IRD1 General transcription factor II-I repeat domain-containing protein 1 is a protein that in humans is encoded by the ''GTF2IRD1'' gene. The protein encoded by this gene contains five GTF2I-like repeats and each repeat possesses a potential helix-lo ...

(GTF2I repeat domain containing protein 1) via a yeast 2 hybrid screen. GTF2I is a gene that encodes the general transcription factor II-1. This specific study showed that GTF2IRD1 is a nuclear protein that is involved transcriptional regulation through chromatin modification. The fact that it exists in the nucleus and was found in neuronal cells correlates with the localization and functional data for FHAD1. Additionally, FHAD1 and GTF2IRD1 interacted through RD2 (repeat domain 2) of GTF2IRD1. RD2 has shown some level of DNA binding activity. FHAD1 was found to interact (

colocalization In fluorescence microscopy, colocalization refers to observation of the spatial overlap between two (or more) different fluorescent labels, each having a separate emission wavelength, to see if the different "targets" are located in the same area of ...

) with

14-3-3 14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and trans ...

protein epsilon via cosedimentation. This protein binds to a number of binding partners, mostly by recognizing

phosphothreonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...

phosphoserine Phosphoserine (abbreviated as SEP or J) is an ester of serine and phosphoric acid. Phosphoserine is a component of many proteins as the result of posttranslational modifications. The phosphorylation of the alcohol functional group in serine to pro ...

motifs.

Clinical Significance

FHAD1 showed differential expression in patients diagnosed with

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...

and

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

Homology and Evolution

FHAD1 has no known

paralogs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

. It has

orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

in the organisms in the following classes:

Mammalia Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

Reptilia Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates (lizards and snakes) and rhynchocephalians ( ...

Aves Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...

Sarcopterygii Sarcopterygii (; ) — sometimes considered synonymous with Crossopterygii () — is a taxon (traditionally a class or subclass) of the bony fishes known as the lobe-finned fishes. The group Tetrapoda, a mostly terrestrial superclass includi ...

Actinopterygii Actinopterygii (; ), members of which are known as ray-finned fishes, is a class of bony fish. They comprise over 50% of living vertebrate species. The ray-finned fishes are so called because their fins are webs of skin supported by bony or h ...

Gastropoda The gastropods (), commonly known as snails and slugs, belong to a large taxonomic class of invertebrates within the phylum Mollusca called Gastropoda (). This class comprises snails and slugs from saltwater, from freshwater, and from land. ...

and

Lingulata Lingulata is a class of brachiopods, among the oldest of all brachiopods having existed since the Cambrian period (). They are also among the most morphologically conservative of the brachiopods, having lasted from their earliest appearance to the ...

. There was significant conservation in the FHA domain in all the organisms in the table below.

The rate of evolution of FHAD1 was compared with that of

fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clo ...

and

cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

and it showed that FHAD1 is a rapidly evolving gene.

References

{{reflist Proteins Genes on human chromosome 1