C-reactive protein

Background

C-Reactive Protein (CRP) is member of the pentraxin family which is characterised by its pentameric architecture and by its calcium-dependent binding of its ligands. Throughout the medical field, the CRP has been used to clinically determine whether or not there is an infection, tissue injury, or an inflammatory response occurring within the body. Thus, CRP is a major acute-phase protein, in which its concentration can reach levels upwards of 10+mg/L ^[1]. In comparison, normal CRP levels within the human body are referenced to be estimated at 0.8mg/L depending on the subject. In a pathophysiological sense, CRP has been researched to be a "significant predictor of future cardiac episodes" ^[2]. With that, CRP is determined to play a specific role in both physiological and pathophysiological aspects within the human body.

Structure

CRP has a mass of 23kDa per subunit with 206 amino acid residues because it is a pentameric protein, which means it is ""^[1]. Functionally, CRP will "bind to [phosphocholine] PCh in a - dependent manner" ^[1]; moreover, CRP has five binding sites for PCh, one on each subunit ^[1]. Some of the amino acids that are directly present in the binding sites include, Glu81, Phe66, and Thr76. The Glu81 forms hydrogen bonds with the nitrogen atom that is within the choline group of the PCh, "Phe66 interacts with three methyl groups of choline" ^[1], and the Thr76 is a crucial aspect in opening the binding site to an appropriate size for the PCh ^[1]. Furthermore, PCh's phosphate group is interactive with two Ca2+ molecules that are bound to the CRP ^[1]. The Ca2+ is the bound ligand to the C-reactive protein with two calcium ions per protomer.

Structurally, each subunit is configured around a central pore and is arranged in a "characteristic 'lectin fold' with a ," and they lie within the PCh binding site facing the "recognition face of the CRP molecule" ^[1]. Regarding the ligand, the calcium ions are crucial for the stability of binding the ligand to the molecule. Moreover, CRP is primarily synthesized within liver hepatocytes; however, the protein can also be synthesized by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes, which are other types of cells within the body ^[1]. Its pentameric structure is "first synthesized as a monomer and then assembled into the pentamer in the endoplasmic reticulum of the source cell" ^[1]. CRP is then retained in the endoplasmic reticulum within hepatocytes and is bound to two carboxylesterases, but while it is in the non-inflammatory state, or resting state, it is slowly released from the endoplasmic reticulum ^[1]. Additionally, "following an increase in inflammatory cytokine levels, the binding of CRP to the carboxylesterases decreases, and the CRP is secreted rapidly" ^[1]. This stimulation is only in response to pro-inflammatory cytokines.

The Human C-reactive protein can also be "irreversibly dissociated into termed monomeric CRP where the free subunits are found at high concentrations of urea and in high temperature with the absence of calcium" ^[1]. This monomeric isoform of CRP is termed mCRP, whereas the pentameric is termed nCRP. Each isoform of CRP is distinguished to have their own biological functions to an inflammatory response ^[1]. One study concluded and "provided evidence that nCRP suppresses the adherence of platelets to neutrophils, whereas mCRP enhances these interactions" within an inflammatory response ^[1]. During the inflammatory response within the body, there is a signaling process where the body calls for protection against the abnormality. Thus, this difference in the two isoforms can be related to this process and their binding to the specific types of "Fcgamma" receptors ^[1]. Explaining this difference, "the mCRP isoform utilizes the low-affinity immune complex binding immunoglobulin G (IgG) receptor called (CD16B) on neutrophils and (CD16a) on monocytes, while nCRP bind to the low-affinity IgG receptor (CD32) ^[1]. Thus, the two isoforms have their own binding processes during the signal process of an inflammatory response. In general, the "nCRP isoform is more directed towards an anti-inflammatory response, whereas the mCRP isoform is particularly involved in pro-inflammatory responses ^[1]. However, there are "antibodies that are not commercially available to date [to detect mCRP levels], so few laboratories can conduct studies investigating the mCRP isoform" ^[1]. Thus, leading to the indication that each isoform is crucial to different abnormalities within the human body.

Medical Applications

During the times of COVID-19, which appeared in the year 2020, pneumonia is one of the biggest worries a person could develop while having the upper respiratory infection. The most common type of bacteria that causes an upper respiratory infection is the Streptococcus pneumoniae bacterium, and it is also the most common culprit of septicemia and meningitis ^[3]. While contracting one of these infections, the CRP will bind to the bacteria through the "Ca2+ dependent reactions with PCh residues" on the bacterial cell walls ^[3]. Structurally, PCh is widely distributed inside and outside of pathogens and in the cellular membranes, which allows CRP to recognize a wide range of pathogenic targets and damaged host cells. This reaction raises the CRP levels within the serum of human blood, allowing for a laboratory test to detect the elevated levels of CRP, indicating that an infection or inflammatory response is occurring within the body.

Human C-reactive protein plays a significant role in the acute phase of defense against pathogens. CRP will specifically bind to the damaged membranes of host cells where there is "an increased proportion of Lysophospholipid ^[4]. The ability of CRP to contribute to the innate immunity within the body allows for it also to prevent autoimmunity ^[4]. It has also been discovered that CRP is a crucial indicator in the complications or outcomes of an individual after suffering a myocardial infarction (heart attack) where "CRP will deposit into the infarcted tissue, and it activates complement" ^[4].. This response triggers the body's "classical complement pathway of innate immunity by activating C1q" ^[1]. The activation of this innate immunity allows for the body to start the healing process within the localized area.

However, CRP levels vary amongst a wide variety of infections or injuries. CRP levels can diminish over 18-20 hours after the stimuli has ended, and the levels can continue to increase if there is a more serious underlying condition such as progressive cancer ^[1]. There are also many more factors that alter the baseline levels of CRP within the body that include "age, gender, smoking status, weight, blood pressure, and lipid levels ^[1]. Baseline CRP levels of an individual can be found around a level of 0.8mg/L in a healthy Caucasian, "but this baseline can vary greatly in individuals due to [the] other factors, [also] including polymorphisms in the CRP gene" ^[1]. Although polymorphisms have been found with the CRP gene, "there are no allelic variations or genetic deficiencies discovered for this gene" ^[1]. A study was conducted with twins that "showed significant heritable components in [the] baseline CRP values that are independent of age and body mass index"^[1]. The study concluded that the CRP levels are roughly 35-40% heritable ^[1]. It is known that CRP levels are elevated due to disease, so the levels cannot be directly reduced through the administration of drugs, but rather, by directly treating the underlying medical condition.

Furthermore, it is widely known that the CRP protein is crucial in the determination of the pathophysiology of the human body. There are multiple benefits for its use in determining different diseases that are occurring within the body. For example, the determination of elevated CRP levels can indicate other types of infections, such as appendicitis, cholecystitis, and pancreatitis. On the other hand, the tests have to be conducted within a specific period once the clinically indicated symptoms have occurred; otherwise, the results will not show any of the biological markers, and the CRP levels will decrease over 12-18 hours.

Human CRP Overall

In conclusion, Human C-reactive protein has been studied for years and has been found to have a substantial effect on modern-day medicine. The C-reactive protein's structure is quite involved within the human body. However, its biological role of being able to protect against infections and to present a biological marker has allowed medical professionals to diagnose and treat patients better clinically. Most of the action that CRP partakes in, whether it be in a pro-inflammatory response or an anti-inflammatory response, is dependent on its own action. Functions regarding CRP are widely unknown still today, but with modern-day technology, the research regarding CRP is continuing to develop and will allow further advances in clinical decision making.

3D Structures of C-reactive protein

Updated on 11-February-2021

1lj7 – hCRP – human

1gnh, 3pvo – hCRP + Ca
3pvn – hCRP + Ca + Zn
3l2y – hCRP + Ca + phosphoethanolamine
1b09 – hCRP + Ca + phosphocholine
4pbo – zCRP – zebrafish
4pbp – zCRP + Ca