TYK2

Also known as

• Tyrosine kinase 2
  
• Non-receptor tyrosine-protein kinase TYK2 
• EC 2.7.10.2
• JTK1
  

 

Physiology

Activated by:

• IFNAR2
  
• Type I interferon signalling
• Type III interferon signalling
  
• IL-6 (Interleukin 6)
• IL-10 (Interleukin 10)
• IL-12 (Interleukin 12)
• IL-23 (Interleukin 23)

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with TYK2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Chronic hepatitis C infection
• Immunodeficiency 35 (IMD35)
• Hyperimmunoglobulin E syndrome (HIES)
• Lymphomatoid Papulosis
• Primary cutaneous anaplastic large cell lymphoma
• Polycythemia vera

These disorders suggest an increased susceptibility to severe infections and malignancies, possibly due to cytokine signalling deficiencies. 

 

Protein profile

• Size = 1187 amino acids
• Molecular mass = 133,650 Da
• Quaternary structure: Interacts with JAKMIP1. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family = Enzyme > Tyrosine kinase > Janus kinase

 

Genetic profile

• Species: Human
• Chromosome: 19
• Band: 19p13.2
• Starts at base pair: 10,350,529
• Ends at base pair: 10,380,572 
• Sequence length (base pairs): 30,043

 

See also

• genecards.org
  
• Interferon
  

IFNAR2

Also known as

• Interferon-alpha/beta receptor beta chain
• Interferon Alpha And Beta Receptor Subunit 2
• Interferon (Alpha, Beta And Omega) Receptor 2
• Type I Interferon Receptor 2
• IFNABR

 

Physiology

IFNAR2 is activated by:

• Type I interferons
  
1. IFN-α
2. IFN-β
3. IFN-ε
4. IFN-κ 
5. IFN-ω
• Type III interferons
1. IFN-λ1
2. IFN-λ2
3. IFN-λ3
4. IFN-λ4

 

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses
  

 

Clinical significance

Disorders associated with IFNAR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Measles as a result of MMR vaccination
  
• Severe HHV6 infection
  
• Immunodeficiency 45 (IMD45)

These disorders suggest an increased susceptibility to severe viral infections, possibly due to an interferon signalling deficiency.

 

Protein profile

• Size (amino acids) = 515
• Molecular mass (Daltons) = 57,75
• Quaternary structure: Heterodimer with IFNAR1. Isoform 1 interacts with the transcriptional factors STAT1 and STAT2. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family: Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 21
• Band: 21q22.11
• Starts at base pair: 33,229,901
• Ends at base pair: 33,265,675
• Sequence length (base pairs): 35,775
  

 

See also

• genecards.org
• Interferon
  

CCR2

Also known as

• C-C Chemokine Receptor Type 2
• C-C Motif Chemokine Receptor 2  
• CD192
• Cluster of differentiation 192
  
• Monocyte Chemoattractant Protein 1 Receptor
• Monocyte Chemotactic Protein 1 Receptor
  

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with CCR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
  

 

Protein profile

• Size (amino acids) = 374
  
• Molecular mass (Daltons) =  41,915
• Quaternary structure: Interacts with ARRB1. Interacts (via extracellular N-terminal region) with beta-defensin DEFB106A/DEFB106B. Interacts with NUP85; the interaction is required for CCR2 clusters formation on the cell membrane and CCR2 signaling.
  
• Protein family = Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 3
• Band: 3p21.31
• Starts at base pair: 46,353,734
• Ends at base pair: 46,360,928
• Sequence length (base pairs): 7195

 

See also

• Chemokines 
• genecards.org

OAS1

Also known as

• 2'-5'-oligoadenylate synthetase 1

 

Laconic summary

• OAS1 is an enzyme. It promotes RNA degradation, to suppress viral infection.

 

Physiology

Upstream events:

• Expression of the OAS1 protein is induced by interferon signalling.
  
• OAS1 is activated by double-stranded RNA.
  

 

Molecular actions

• Activation of enzymes called RNASELs (latent ribonucleases).

 

Downstream outcomes:

• Degradation of host RNA within the cell. (Unavoidable consequence).
• Degradation of viral RNA within the cell. (Antiviral defence).
• Suppression of host protein synthesis. (Unavoidable consequence).
  
• Suppression of viral protein synthesis. (Antiviral defence).
  
• Suppression of viral RNA replication. (Antiviral defence).

 

Biological functions

• Suppression of viral replication.
  

 

Clinical significance

Disorders associated with OAS1 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology 
• Herpes simplex infection
• Yellow fever
• Infantile-onset pulmonary alveolar proteinosis hypogammaglobulinaemia
• Pulmonary alveolar proteinosis with hypogammaglobulinaemia
• Microphthalmia with limb anomalies

 

Protein profile

• Size (amino acids) = 400
  
• Molecular mass (Daltons) = 46,029
  
• Quaternary structure: Monomer. Homotetramer.
• Protein family = Enzyme. 2'-5'-oligoadenylate synthase.

 

Genetic profile

• Species: Human
• Chromosome: 12
• Band: 12q24.13
• Starts at base pair: 112,906,783
• Ends at base pair: 112,933,222
  
• Sequence length (base pairs): 26,439

 

See also

• genecards.org
• Interferon
  

DPP9

Also known as

• Dipeptidyl peptidase 9
• Dipeptidyl Peptidase-Like Protein 9
  

 

Physiology

Biological functions

• Cell adhesion

 

Clinical significance

Disorders associated with DPP9 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Idiopathic pulmonary fibrosis
• Chronic nasopharyngitis 
  

 

Protein profile

• Size (amino acids) = 863
  
• Molecular mass (Daltons) = 98,263
  
• Quaternary structure: Homodimer.
  
• Protein family: Enzyme > Serine protease
  

 

Genetic profile

• Species: Human
• Chromosome: 7
• Band: 7q36.2
• Starts at base pair: 153,887,097
• Ends at base pair: 154,894,285
• Sequence length (base pairs): 49,450

 

See also

• genecards.org
• DPP4 (Dipeptidyl peptidase-4)

ACE2

Also known as

• Angiotensin-converting enzyme 2

 

Laconic summary

• ACE2 is an enzyme involved in RAAS. Several viruses exploit it to enter host cells.

 

Physiology

• Catalyses the conversion of angiotensin II (a vasoconstrictor) into 'angiotensin 1-7' (a vasodilator).
• Lowers blood pressure.

See: Renin-Angiotensin-Aldosterone system (RAAS).

• Renin
  
• Angiotensin
• Angiotensinogen
  
• Angiotensin I
• Angiotensin II
• Angiotensin (1-7)
• Angiotensin-converting enzyme
• Aldosterone
  

Clinical significance

Pathogenicity

Exploited to facilitate entry into host cells, by pathogens:

• SARS-CoV2
• Coronavirus Disease 2019 (COVID-19)
  
• Pathophysiology
• SARS-CoV
• Severe Acute Respiratory Syndrome (SARS)
• HCoV-NL63
  

Related genetic disorders:

• Hartnup disorder

Related medications:

• Angiotensin Converting Enzyme Inhibitors (ACE-Is)
  
• Angiotensin Receptor Blockers (ARBs)

ACE2 is upregulated in patients who take ACE-i / ARB therapies.

New therapeutics

• Recombinant ACE2 may be an effective therapeutic in the management of Acute Respiratory Distress Syndrome.

 

Protein profile

• Size (amino acids) = 805
  
• Molecular mass (Daltons) = 92,463
  
• Quaternary structure: Homodimer.
• Protein family = Enzyme > Metalloenzyme (zinc-containing)
  

 

Genetic profile

• Species: Human
• Chromosome: X
• Band: Xp22.2
• Starts at base pair: 15,561,033
• Ends at base pair: 15,602,148
• Sequence length (base pairs): 41,116

 

See also

• genecards.org

Ionising radiation

Fundemental science article

Also known as

• Commonly called "radiation"
  

Physics

The structure of matter

• Matter is made of atoms, ions and electrons.
• Every atom has a central component called a nucleus. The nucleus is orbited by electrons. 
• The nucleus is made of protons and neutrons. The number of protons in an atom is equal to the number of electrons. The number of protons is known as the atomic number.
• The number of protons and neutrons together is known as the mass number.
• Each proton and neutron is comprised of subatomic particles called quarks.
• One of the fundemental interactions of the universe is known as the 'strong interaction'. It is responsible for binding together neutrons and protons in the atomic nucleus. This interaction occurs as an ongoing quark exchange between protons and neutrons. 
• As the proton number gets higher, the neutron number usually rises too.
• If there is a gain of an electron without a gain of a proton, an atom becomes a negative ion. 
• If there is a loss of an electron without the loss of a proton, an atom becomes a positive ion.
• Each element has a specific number of protons. Different atoms of the same element can have a different neutron number. These are known as isotopes of that element.
• Some elements and isotopes are very unstable systems. Generally, the higher the mass number, the more unstable the atom is.

Nuclear decay, radioactivity

• One of the fundemental interactions of the universe is known as the 'weak interaction'.
• Through this interaction, atomic nuclei can decay to a more stable state, producing a new element or a new isotope.
• Nuclear decay events result in the expulsion of alpha particles (high-energy helium-4 nuclei), beta particles (high-energy electrons), positrons (anti-electrons) or gamma rays (high-energy photons). The new isotope produced by the decay is more stable.
• Positrons interact with electrons in a process called annihilation. Both particles are destroyed but due to mass-energy conservation, symmetrical gamma rays (high-energy photons) are emitted.
• Radioisotopes undergo nuclear decay at perfectly regular intervals. This is the principle behind atomic clocks.
• The half-life of an isotope X is that amount of time that it will take for 100kg of isotope X to decay to 50kg of isotope X. The half-life remains constant for an isotope, but the emitted dose of radiation decays exponentially with time. The half-lives of some radioisotopes are billions of years.
• Alpha particles, beta particles, and gamma rays are highly energetic and ionising.  
• Ionising radiation can turn atoms into ions. This can disrupt the chemical bonds of any molecule.
• As air becomes ionised, there may be a metallic taste, a smell of ozone, or an ionised-air glow.
• Ionisation events can be detected by instruments such as the Geiger–Müller counter. These instruments display a count per second.

Activity

• Activity of a radioactivity material can be expressed as Bq (Becquerel). 1 Bq is equivalent to 1 nuclear decay per second. The greater the mass of the material, the greater the measured activity.
• The mass of radioactive material and the activity fall as the material decays.
• A material with a half-life of 100 years will have decayed to half the mass of that radioisotope after 100 years.
• Due to long half-lives and large amounts of contamination, some areas on the planet will continue to emit significant amounts of ionising radiation for thousands of years. They must remain isolated and contained to prevent future disease.

 

Doses

• When measuring ionising radiation dose, the Sievert value reflects the energy (in joules) transferred to 1kg of matter each second.
• 1 Sv = 1000 mSv.
• Approximately 1 gray per second (if gamma radiation).
• Approximately 100 rem per second.
• Approximately 100 rad per second (if gamma radiation).
• Approximately 360,000 roentgen per hour.
• Approximately 1 watt per kilogram.
• Approximately 1 joule per kilogram per second.
• The average person in the USA receives an estimated effective dose of about 3 mSv (milliSievert) per year from background (natural) radiation.
• A dose of 4-5 Sieverts or more, absorbed within a short time period, causes death in 50% of patients, within 30 days.

 

Sources of ionising radiation

Mild 

• Electronic devices
• Cosmic rays
• Natural radon gas stores

Moderate

• Radiological imaging
• Radiotherapy devices
• Brachytherapy
• Solar radiation (sunlight)

Severe

• Waste from nuclear power plants
• Use of nuclear weapons

 

Pathophysiology

• High energy ionising radiation causes damage to all exposed biological structures.
• The energy of the radiation can result in tissue damage similar to thermal or electrical burns. A sufficiently high dose will vaporise living tissue.
• The most radiation-sensitive structures within cells are the genetic materials. DNA and RNA are easily damaged or destroyed, leaving the cells incapable of functional protein synthesis.
• Successful mitosis cannot occur so destroyed cells are not replaced.
• The cell cannot repair physical damage.
• Many cells undergo apoptosis (programmed cell death).
• Tissues start to break apart.
• Any DNA damage can persist in the long-term to cause future cell dysfunction including malignant transformation.

Exposure to ionising radiation can cause:

• Acute radiation syndrome (ARS) 
• Radiation injuries
• Abortion (if pregnant)
• Birth defects (if pregnant)
• Malignancy
• Aplastic anaemia

 

Prevention of disease

• Use of a Geiger–Müller counter: Each count represents one ionisation event (i.e. one expulsion of an ionising ray or particle). These can be heard as audible clicks.
• Use of protective clothing and shielding. Lead is a useful material for absorbing ionising radiation.
• Exposure to radioactive contaminants could cause ARS, pregnancy abortions and it increases the risk of developing cancer. For this reason:
• Any fabrics, animals, crops or fluids exposed to radioactive materials must be safely identified, gathered, destroyed and contained.
• Any individuals exposed to radioactive materials must be quarantined. Contaminated corpses must be buried in coffins designed to safely contain them.
• Heavily contaminated areas must be evacuated.

 

History of radiation injuries